Stabilized compositions containing alkaline labile drugs

ABSTRACT

A stabilized bioadhesive composition containing an alkaline labile drug and a method for its preparation are provided. In one aspect, the composition is a hot-melt extruded (HME) composition comprising a preformed excipient mixture comprising an acidic component and an alkaline thermoplastic matrix-forming material, e.g. polymer. The excipient mixture is formed before blending with an alkaline labile drug. The blend is then hot-melt extruded to form the HME composition. By so doing, the acidic component is able to neutralize or render moderately acidic the excipient mixture. This particular process has been shown to substantially reduce the degradation of an alkaline labile drug during hot-melt extrusion. The excipient mixture softens or melts during hot-melt extrusion. It can dissolve or not dissolve drug-containing particles during extrusion. Various functional excipients can be included in the carrier system to improve process performance and/or improve the chemical or physical properties of the HME composition.

FIELD OF THE INVENTION

The present invention concerns a hot-melt extruded (HME) compositioncomprising an alkaline-labile drug and an alkaline thermoplasticpolymer. The invention also concerns a process for preparing a HMEpharmaceutical composition having improved drug stability.

BACKGROUND OF THE INVENTION

Buccal delivery of therapeutic agents is a highly desirable alternativemode of administration for drugs that undergo a significant amount offirst pass metabolism when administered orally. Steroids, in particulartestosterone, are available in transdermal or transmucosal deliverysystems.

Testosterone can be admitted transdermally, transmucosally or in a bodycavity using a dosage form such as a patch, implant, film, gel, cream,ointment, or suppository. ANDRODERM® (Watson Labs) and TESTODERM® (AlzaCorp.) are exemplary extended release transdermal films. According toits PDR package insert, ANDRODERM drug reservoir layer includestestosterone, alcohol, glycerin, glycerol monooleate, methyl laurate,acrylic acid copolymer and water.

Many researchers have utilized hot-melt extrusion techniques to producepharmaceutical preparations in various forms. Zhang and McGinityutilized hot-melt extrusion to produce sustained release matrix tabletswith poly(ethylene oxide) (PEO) and polyvinyl acetate, and moregenerally non-film preparations with PEO (Zhang, F. and J. W. McGinity,Properties of Sustained-Release Tablets Prepared by Hot-Melt Extrusion.Pharmaceutical Development and Technology, 1999. 4(2): p. 241-250;Zhang, F. and J. W. McGinity, Properties of Hot-Melt ExtrudedTheophylline Tablets Containing Poly(Vinyl Acetate). Drug Developmentand Industrial Pharmacy, 2000. 26(9): p. 931-942; Robinson, J. R., J. W.McGinity, and P. Delmas, Effervescent granules and methods for theirpreparation. June 2000 and November 2003, Ethypharm: U.S. Pat. No.6,071,539 and 6649186.) Kothrade et al. (Kothrade, S., et al., Methodfor producing solid dosing forms. 2003: U.S. Pat. No. 6,528,089WO9927916 DE19753298 EP1035841) demonstrated a method of producing soliddosage forms of active ingredients in a vinyllactam co-polymeric binderby hot-melt extrusion. Aitken-Nichol et al. (Aitken-Nichol, C., F.Zhang, and J. W. McGinity, Hot Melt Extrusion of Acrylic Films.Pharmaceutical Research, 1996. 13(5): p. 804-808) used hot-meltextrusion methods to produce acrylic polymer films containing the activelidocaine HCl. Grabowski et al. (Grabowski, S., et al., Solid activeextrusion compound preparations containing low-substitutedhydroxypropylcellulose. 1999: U.S. Pat. No. 5,939,099 WO9625151DE19504832 EP0809488) produced solid pharmaceutical preparations ofactives in low-substituted hydroxypropyl cellulose using hot-meltextrusion techniques. Repka and McGinity (Repka, M. A. and J. W.McGinity, Hot-melt extruded films for transmucosal & transdermal drugdelivery applications. Drug Delivery Technology, 2004. 4(7): p. 40, 42,44-47) used hot-melt extrusion processes to produce bioadhesive filmsfor topical and mucosal adhesion applications for controlled drugdelivery to various mucosal sites (Repka, M. A., S. L. Repka, and J. W.McGinity, Bioadhesive hot-melt extruded film for topical and mucosaladhesion applications and drug delivery and process for preparationthereof. Apr. 23, 2002: U.S. Pat. No. 6,375,963; Breitenbach, J. and H.D. Zettler, Method for producing solid spherical materials containing abiologically active substance. 2000: WO 0024382). Robinson et al.produced effervescent granules with controlled rate of effervescenceusing hot melt extrusion techniques. Breitenbach and Zettler(Breitenbach, J. and H. D. Zettler, Method for producing solid sphericalmaterials containing a biologically active substance. 2000: WO 0024382)produced solid spherical materials containing biologically activesubstances via hot-melt extrusion. De Brabander et al. (de Brabander,C., C. Vervaet, and J. P. Remon, Development and evaluation of sustainedrelease mini-matrices prepared via hot melt extrusion. Journal ofControlled Release, 2003. 89(2): p. 235-247; de Brabander, C., et al.,Bioavailability of ibuprofen from hot-melt extruded mini-matrices.International Journal of Pharmaceutics, 2004. 271(1-2): p. 77-84)demonstrated sustained release minimatrices by utilizing hot-meltextrusion techniques.

Various different drugs have been included in HME compositions. Undergiven circumstances, stable HME compositions can be made. However, thechemical stability of a drug included within the matrix of the HMEcomposition is highly variable when comparing different combinations ofmatrix-forming material, drugs, excipients and processing conditions.

Various different thermoplastic materials have been used as thematrix-forming material in HME compositions. These materials aregenerally, but not necessarily, polymeric. One of the more desiredpolymers for this use is PEO, because PEO-based HME compositions arebioadhesive. They adhere to mucosal tissue when placed in contact withit. Thus, PEO-based HME compositions can be used for transmucosaldelivery of therapeutic agents.

U.S. Pat. No. 6,072,100 to Mooney et al. discloses an extrudedcomposition containing “a thermoplastic water-soluble polymer selectedfrom the group consisting of hydroxypropyl cellulose and polyethyleneoxide; a water-soluble polymer derived from acrylic acid; medicament;and plasticizer.”

U.S. Pat. No. 6,375,963 to Repka et al. discloses a bioadhesive hot-meltextruded film composition comprising a water swellable or water solublethermoplastic polymer (such as HPC or PEO) and a bioadhesive polymer(such as polycarbophil, carbopol, a co-polymer of methyl vinyl ether andmaleic acid or anhydride, one or more acrylic polymers, one or morepolyacrylic acids, copolymers of these polymers, a water soluble salt ofa co-polymer of methyl vinyl ether and maleic acid or anhydride, acombination thereof and their salts). In some embodiments, the filmcontains an organic acid, a superdisintegrant, a super-absorbent and/oran antioxidant.

Even with the significant advances in the art provided by the '963patent, PEO may be prone to degradation according to the hot-meltextrusion conditions to which it is exposed. The product literature forPOLYOX® (the trademark for polyethylene oxide as sold by Dow Chemical)indicates that BHT and vitamin-E (D-α-tocopheryl) are suitableantioxidants for use in stabilizing hot-melt extruded compositions basedupon PEO. Huang et al. (Chinese Pharmaceutical Journal, (2003) 55/6(463-472) disclose the advantageous use of parabens and BHT in hot-meltextruded films made from PEO. Repka et al. (International Journal ofPharmaceutics, (20 Jul. 2000) 202/1-2, 63-70) disclose the advantageoususe of Vitamin E TPGS in hot-melt extruded films made from PEO.

Crowley et al. (Dissertation Abstracts International, (2003) Vol. 65,No. 1B, p. 178. Order No.: AAI3119662. 264 pages; Biomaterials, (NOV2002) Vol. 23, No. 21, pp. 4241-4248) disclose the stabilization ofhot-melt extruded films containing PEO as the thermoplastic matrix byinclusion of Vitamin-E-TPGS and Vitamin-E-succinate. The use of lowmolecular weight PEO as a processing aid for high molecular weight PEOis disclosed. They also disclose that ascorbic acid (0.5-1.0%) degradesPEO during hot-melt extrusion suggesting that ascorbic acid should notbe included in formulations containing PEO. Crowley et al. do notdisclose the use of testosterone or another steroid in the film.

Moreover, a drug included in a HME composition may also be prone todegradation. For example, testosterone is prone to degradation inalkaline conditions. Its major degradants include6-beta-hydroxytestosterone, 4-Androsten-16-alpha-ol-3,17-dione,Androstenedione, Epi-testosterone. So, if testosterone, or any otheralkaline labile drug were to be included in a HME composition, such acomposition would necessarily exclude alkaline materials. Alkalinematerials often have desirable physical or clinical properties. So theirexclusion from HME compositions is not desirable.

It would be an advancement in the art to develop a method ofmanufacturing a HME composition comprising an alkaline matrix-formingmaterial and an alkaline labile drug.

SUMMARY OF THE INVENTION

The present invention seeks to overcome some or all of the disadvantagesinherent in the above-mentioned compositions and methods. The inventionresolves the problem of the instability of alkaline labile drugs, whichthe inventors have observed during hot-melt extrusion with alkaline orneutral thermoplastic matrices. It has been found that PEO, which isalkaline, can increase the degradation of testosterone duringprocessing. Neutralization of the PEO prior to mixing with thetestosterone was found to decrease the amount of impurities formedduring hot-melt extrusion.

The inventors have discovered that PEO can be used as the matrix-formingthermoplastic if the PEO is wet or dry granulated with an acidiccomponent and optionally one or more other excipients to form anexcipient mixture prior to the addition of an alkaline labile drug. Theexcipient mixture is then mixed with testosterone and other excipientsthat can be included in the formulation and then extruded. Therefore,the invention provides a method of preparing a therapeutic stabilizedbioadhesive hot-melt extruded composition comprising an alkaline labiledrug, an alkaline thermoplastic water soluble or swellable polymer(which is optionally bioadhesive), and an acidic component, the processcomprising the steps of: mixing the acidic component with the alkalinethermoplastic, water soluble or swellable polymer to form an excipientmixture, and then blending the excipient mixture with the alkalinelabile drug. The mixing step can be wet granulation step.

A key aspect of the invention requires neutralization or moderateacidification of the alkaline thermoplastic polymer (e.g. PEO) with anacidic component. The polymer is neutralized by wet or dry granulatingit with the other materials, such as poloxamer, to be included in thematrix, and the acidic component, such as citric acid and/or an acidicpolymer, such as CARBOPOL®. Wet granulation is conducted with water (orbuffer) or an aqueous alcohol solution. After this excipient mixture hasbeen prepared, it is optionally dried and then blended with the activeagent (such as testosterone) followed by hot-melt extrusion of theentire mixture.

When wet granulation is employed to prepare the excipient mixture, anaqueous medium is used. Exemplary aqueous medium includes water, buffer,or water (or buffer) containing organic solvent. In one embodiment, theorganic solvent is water miscible. Suitable water miscible solventsinclude methanol, ethanol, propanol, iso-propanol, benzyl alcohol,cyclomethicone, glycerin, propylene glycol, low molecular weightpolyethylene glycol, simethicone, and others known to those of ordinaryskill in the art.

The acidic component can be mixed with the alkaline polymer as a liquidor solid. For example, the acidic component may be dissolved, suspendedor wet with the aqueous medium used for wet granulation. Alternatively,the acidic component can be added in solid form.

In one embodiment, the acidic component will dissolve during the wetgranulation step. In another embodiment, it will not. For example, whenthe acidic component is an acidic polymer, it may or may not dissolveduring wet granulation. It is preferred that the acidic component willat least become hydrated (or wet) with the aqueous medium. In anotherembodiment, the acidic component is mixed with the alkaline polymeruntil homogeneity during the wet or dry granulation step.

According to one embodiment, a second matrix forming material, such aspoloxamer, a Vitamin E based antioxidant, and an acidic component arewet granulated with the alkaline thermoplastic polymer, such as PEO, toform a neutralized excipient mixture. This mixture is dried(optionally), mixed with drug, and then hot-melt extruded.Alternatively, the second matrix forming material, antioxidant andalkaline thermoplastic polymer are wet granulated and then the acidiccomponent is mixed in to form the neutralized excipient mixture, whichis then processed as above.

It has also been found that greater degradation also occurs when thetime of exposure of the alkaline labile drug, such as testosterone (Ts),to heat is increased. Thus, another aspect of the invention requiresminimizing the heat exposure of testosterone so as to minimize theformation of its degradants during processing. This is done by selectingthe appropriate processing conditions to minimize extrusion temperatureand duration of extrusion time and to decrease the matrix viscosity.

The composition of the invention can be a film, multi-layered film(laminate), rod, pellet, bead, tablet, pill, granulate, powder, capsule,tube, strand, or cylinder and can be further processed into a powder,pellets, or powder coatings for application on various substrates. Alaminate will comprise at least two layers: a bioadhesive drug reservoirlayer and a backing layer. In one embodiment, the backing layer of thelaminate also includes an acidic component, so as to minimize anyinterfacial degradation that might occur at the interface of thereservoir layer and the backing layer.

One embodiment of the invention provides a process for preparing astabilized bioadhesive hot-melt extruded laminate comprising abioadhesive hydrophilic reservoir layer comprising an alkaline labiledrug, an alkaline matrix-forming polymer and an acidic component; and ahydrophobic low permeability backing layer, the process comprising thesteps of:

wet or dry granulating at least one water swellable or water solublealkaline thermoplastic polymer, an antioxidant, at least one bioadhesivepolymer, at least one acidic component, optionally one or morehydrophobic polymers, optionally one or more hydrophilic polymers, andoptionally one or more other excipients to form an excipient mixturehaving a solution pH (when dissolved) of about 7 or less or less thanthe pH where the alkaline labile drug degrades;

mixing the excipient mixture with an alkaline labile drug to form abioadhesive thermoplastic hydrophilic first composition;

providing a thermoplastic hydrophobic second composition comprising atleast one hydrophobic polymer, a plasticizer, optionally one or morehydrophilic polymers, and optionally at least one acidic component;

coextruding the first composition and the second composition to form abioadhesive bi-layered hot-melt coextruded laminate comprising abioadhesive hydrophilic reservoir layer and a hydrophobic lowpermeability backing layer, respectively.

Another aspect of the invention provides a process for preparing astabilized bioadhesive hot-melt extruded laminate comprising abioadhesive hydrophilic reservoir layer comprising an alkaline labiledrug, an alkaline matrix-forming polymer and an acidic component; and ahydrophobic low permeability backing layer, the process comprising thesteps of:

wet or dry granulating at least one water swellable or water solublealkaline thermoplastic polymer, an antioxidant, at least one bioadhesivepolymer, at least one acidic component, optionally one or morehydrophobic polymers, optionally one or more hydrophilic polymers, andoptionally one or more other excipients to form an excipient mixturehaving a solution pH (when dissolved) of about 7 or less or less thanthe pH where the alkaline labile drug degrades;

mixing the excipient mixture with an alkaline labile drug to form abioadhesive thermoplastic hydrophilic first composition;

providing a thermoplastic hydrophobic second composition comprising atleast one hydrophobic polymer, a plasticizer, optionally one or morehydrophilic polymers, and optionally at least one acidic component;

extruding the first composition to form a bioadhesive hydrophilicreservoir layer;

extruding the second composition to form a hydrophobic low permeabilitybacking layer; and

laminating the reservoir layer to the backing layer to form thelaminate.

Yet another aspect of the invention provides a process for preparing astabilized bioadhesive bilayered laminate comprising a bioadhesivehydrophilic reservoir layer comprising an alkaline labile drug, analkaline matrix-forming polymer and an acidic component; and ahydrophobic low permeability backing layer, the process comprising thesteps of:

wet or dry granulating at least one water swellable or water solublealkaline thermoplastic polymer, an antioxidant, at least one bioadhesivepolymer, at least one acidic component, optionally one or morehydrophobic polymers, optionally one or more hydrophilic polymers, andoptionally one or more other excipients to form an excipient mixturehaving a solution pH (when dissolved) of about 7 or less or less thanthe pH where the alkaline labile drug degrades;

mixing the excipient mixture with an alkaline labile drug to form abioadhesive thermoplastic hydrophilic first composition;

extruding the first composition to form a bioadhesive hydrophilicreservoir layer;

providing a thermoplastic hydrophobic second composition comprising atleast one hydrophobic polymer, a plasticizer, optionally one or morehydrophilic polymers, and optionally at least one acidic component; andeither hot-melt extruding the second composition onto the reservoirlayer to form a bioadhesive bi-layered laminate;

hot-melt extruding the second composition to form a hydrophobic lowpermeability backing layer and subsequently laminating the reservoirlayer and the backing layer together to form a bioadhesive bi-layeredlaminate; or

casting the second composition onto the reservoir layer to form abioadhesive bi-layered laminate.

Another aspect of the invention provides a process for the preparationof a stabilized bioadhesive hot-melt extruded composition comprising analkaline labile drug, an alkaline matrix-forming polymer and an acidiccomponent, the process comprising:

wet or dry granulating at least one water swellable or water solublealkaline thermoplastic polymer, an antioxidant, at least one bioadhesivepolymer, at least one acidic component, optionally one or morehydrophobic polymers, optionally one or more hydrophilic polymers, andoptionally one or more other excipients to form an excipient mixturehaving a solution pH (when dissolved) of about 7 or less or less thanthe pH where the alkaline labile drug degrades;

mixing the excipient mixture with an alkaline labile drug to form abioadhesive thermoplastic hydrophilic composition; and hot-meltextruding the hydrophilic composition to form the bioadhesive hot-meltextruded composition.

The compositions can be optionally dried, as appropriate, either priorto the addition of the alkaline labile drug and/or prior to extrusion.For example, the excipient mixture can be dried prior to conductingmixing with the alkaline drug or the bioadhesive thermoplastichydrophilic composition can be dried prior to hot-melt extrusion.

The wet granulation can be conducted with water, buffer, or aqueousalcohol. The granulation fluid optionally contains an acidic component.

The acidic component can be an acidic polymer (such as a bioadhesivepolymer), inorganic acid, mineral acid or an organic acid or mixturesthereof. For example, the bioadhesive polymer can be the acidiccomponent.

The wet granulation step can be conducted in various different ways. Forexample, the wet granulation step can be conducted by first wetgranulating a poloxamer, an antioxidant, PEO and an organic acid andthen adding a bioadhesive polymer. Alternatively, the wet granulationstep can be conducted by first mixing an aqueous solution of organicacid and hydrophilic polymer with an alcohol solution of antioxidant andthen adding PEO and then adding a bioadhesive polymer.

The composition of the bioadhesive thermoplastic hydrophilic compositioncan vary. For example, it can comprise two or more thermoplastic andwater swellable, water soluble or water erodible polymers, and/or it cancomprise two or more water swellable, water erodible or water solublealkaline thermoplastic polymers. PEO is an exemplary bioadhesivealkaline thermoplastic water soluble or water erodible polymer. In someembodiments, the water swellable or water soluble alkaline thermoplasticpolymer is a bioadhesive polymer.

The composition of the excipient mixture can vary. For example, ahydrophilic polymer can be present in the excipient mixture, anotherhydrophobic polymer can be present in the excipient mixture.

The composition of the backing layer can vary. For example, it cancomprise two or more different hydrophobic polymers.

In some embodiments, the laminating step is heat-catalyzed lamination,and/or the laminating step comprises the steps of placing an adhesivebetween the reservoir layer and the backing layer followed by pressingof the two layers together.

If the reservoir and backing layers of the laminate are coextruded orextruded individually (be it sequentially or concurrently) andsubsequently laminated, the layers preferably comprise at least onepolymer in common; however, the layers will retain their individualcharacteristics of hydrophobicity and hydrophilicity. The reservoir andbacking layers optionally possess approximately the same melt flow index(melt flow rate, melt flow rate, melt index, meaning that their meltflow indices will fall within individual predefined ranges and thatthose ranges overlap at least to some predefined extent.

When the HME composition includes testosterone, it can be used to treatone or more disorders associated with testosterone deficiency, e.g.hypogonadism, Peyronie's disease, priapism, impotence, erectiledysfunction, reduced libido, loss of muscle mass, etc. The method of useincludes the transdermal, preferably the buccal, administration of abioadhesive hot-melt extruded composition comprising testosterone incontrolled release form. During use, the bioadhesive layer absorbs waterfrom saliva and begins to release testosterone in a controlled manner.

The HME composition can be formulated to provide a variety of drugrelease profiles to most sites of administration.

The present invention also includes pharmaceutical formulationscomprised of active compounds finely and homogenously dispersed in oneor more polymeric carriers that are produced by hot-melt extrusiontechniques. Such preparations can include solid dispersions, glasssolutions, molecular dispersions, and solid solutions. The inventionalso provides pharmaceutical formulations wherein the active agent(active compound) is provided in neat form (meaning not containingexcipients) and subsequently employed in the process as detailed herein.

In some embodiments, the pharmaceutical composition is formulated suchthat drug therein may be dissolved during extrusion.

Fine particles of drug made by known processes can be incorporated intothe claimed pharmaceutical composition. Examples include micronizationand milling processes. Drug-containing particles are dispersed withinthe matrix via hot-melt extrusion.

In some embodiments, the thermoplastic matrix-forming material isselected from the group consisting of polyethylene oxide; polypropyleneoxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate; PLA,PLGA, acrylate and methacrylate copolymers; polyethylene;polycaprolactone; polyethylene-co-polypropylene; alkylcelluloses such asmethylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, andhydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropyl methylcellulose; starches, pectins;polysaccharides such as tragacanth, gum arabic, guar gum, sucrosestearate, xanthan gum, lipids, waxes, mono, di, and tri glycerides,cetyl alcohol, steryl alcohol, paraffin waxes and the like, hydrogenatedvegetable and castor oil, glycerol monosterate, enteric polymers such asCAP, HPMC AS, shellac, and a combination thereof.

Release of drug from the HME composition can vary. In some embodiments,the composition (or dosage form) provides an immediate or rapid releaseof therapeutic compound after exposure to an environment of use. Inother embodiments, the pharmaceutical composition (or dosage form)provides a delayed release of therapeutic compound after exposure to anenvironment of use.

The pharmaceutical dosage form or composition described herein can beformulated for transdermal, transmucosal, buccal, rectal, pulmonary,nasal, vaginal, ocular, peroral, oral, intestinal or otic drug delivery,or as an implantable drug delivery device.

The invention also includes combinations of two or more of the differentembodiments disclosed herein.

BRIEF DESCRIPTION OF THE FIGURES

The following figures form part of the present description and describeexemplary embodiments of the claimed invention. The skilled artisan willbe able, in light of these figures and the description herein, topractice the invention without undue experimentation.

FIG. 1 depicts a cross-sectional front elevation of an exemplaryembodiment of a mono-layered hot-melt extruded composition according theinvention.

FIG. 2 depicts a cross-sectional front elevation of an exemplaryembodiment of a bi-layered hot-melt extruded composition according theinvention.

FIG. 3 depicts a cross-sectional front elevation of an exemplaryembodiment of a tri-layered hot-melt extruded composition according theinvention.

FIGS. 4 a and 4 b depict release profiles for various different extendedrelease HME compositions made according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a stabilized HME composition comprising analkaline-labile drug, a thermoplastic bioadhesive matrix, an acidiccomponent and optionally one or more excipients. The matrix comprisesone or more alkaline thermoplastic polymers, one or more bioadhesivepolymers, or a combination thereof. The HME composition comprises abioadhesive hot-melt extrudable excipient composition comprising analkaline thermoplastic bioadhesive polymeric matrix, an acidic componentand optionally one or more excipients, wherein the excipient compositionhas a solution pH of 7.0 or less when placed in water. When an alkalinethermoplastic bioadhesive matrix is mixed with an acidic component itwill form a non-alkaline thermoplastic bioadhesive matrix, meaning thatthe matrix will have a pH of 7 or less when placed in water. Theexcipient composition has a neutral to moderately acidic pH (2-7). Analkaline labile drug, and optionally one or more other excipients, ismixed with the excipient composition, and the mixture is hot-meltextruded to form the stabilized HME composition.

The term hot-melt extrusion or hot-melt extruded is used herein todescribe a process whereby a composition is heated and/or compressed toa molten (or softened) state and subsequently forced through an orificein a die where the extruded product is formed into its final shape inwhich it solidifies upon cooling. The blend is conveyed through one ormore heating zones typically by a screw mechanism. The screw or screwsare rotated by a variable speed motor inside a cylindrical barrel whereonly a small gap exists between the outside diameter of the screw andthe inside diameter of the barrel. In this conformation, high shear iscreated at the barrel wall and between the screw fights by which thevarious components of the powder blend are well mixed and disaggregated.The die can be a dual manifold, multi-manifold or feedblock style die.As used herein, the term extrudate refers to a HME composition. The term“coextrusion” is taken to mean an extrusion process in which at leasttwo different melt compositions are extruded substantiallysimultaneously through a dual confining orifice to form respective firstand second layers of a laminate, whereby the sum total cross-sectionalarea of the two layers corresponds substantially to the cross-sectionalarea of the exit orifice in the extrusion die. The term “lamination” istaken to mean an extrusion process in which at least two differentlayers are hot-melt extruded and combined after exiting the extrusionorifice and then bonded by a set of opposing rollers.

The term “hot-melt extrudable” is taken to mean that a material orcomposition can be hot-melt-extruded with no significant thermaldegradation, e.g. less than 5% wt. or less than 10% wt. degradation. Theterm “thermally processable” is taken to mean a material or compositionthat softens or melts at the extrusion processing temperature with nosignificant thermal degradation.

FIG. 1 depicts a conceptual cross-sectional front elevation of anexemplary monolithic hot-melt extruded composition (1) comprising a drugreservoir (2) according to the invention. The extrudate prepared asdetailed herein provides improved stability of an alkaline labile drugwithin a matrix comprising an alkaline thermoplastic polymer. The drugreservoir comprises an alkaline labile drug and a bioadhesivethermoplastic matrix, wherein the matrix comprises an acidic component(or acidifying agent), an alkaline polymer, a bioadhesive polymer, athermoplastic polymer, and optionally one or more other excipients. Inother words, the matrix comprises an alkaline thermoplastic and/orbioadhesive matrix-forming material, an acidic component and optionallyone or more other excipients.

The matrix of the present pharmaceutical composition includes amatrix-forming material such as a thermal binder, a pressure softenablebinder, or a combination thereof. At least one polymeric binder in thematrix is a bioadhesive polymer. At least one polymer in the matrix isan alkaline polymer prior to treatment with an acidic component.

Exemplary thermal binders include: polyethylene oxide; polypropyleneoxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate;acrylate and methacrylate copolymers; polyethylene; polycaprolactone;polyethylene-co-polypropylene; alkylcelluloses such as methylcellulose;hydroxyalkylcelluloses such as hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, andhydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropyl methylcellulose; starches, pectins;PLA and PLGA, polyesters (shellac), wax such as carnauba wax, beeswax;polysaccharides such as cellulose, tragacanth, gum arabic, guar gum, andxanthan gum.

A specific embodiment of the binder is poly(ethylene oxide) (PEO), whichcan be purchased commercially from companies such as the Dow ChemicalCompany and Sumitomo Seika, which market PEO exemplary grades with anaverage molecular weight from about 100,000 to about 8,000,000. Some ofthe grades of PEO that are suitable for use in this invention aredescribed in the tables below, which differentiate the grades accordingto their approximate molecular weights and solution viscosity.

Approximate Viscosity Range Molecular Aqueous Solution Trade Name Weightat 25° C., mPa · s WSR N-10 100,000 30-50 (5% solution) PEO-1Z150,000-400,000 50-200 (5% solution) WSR N-80 200,000 55-90 (5%solution) WSR N-750 300,000 600-1,200 (5% solution) WSR N-3000 400,0002250-4500 (5% solution) WSR-205 600,000 4,500-8,800 (5% solution) PEO-3Z  600,000-1,100,000 2,500-5,500 (5% solution) WSR-1105 900,0008,800-17,600 (5% solution) WSR N-12K 1,000,000 400-800 (2% solution)PEO-8Z 1,700,000-2,200,000 20-70 (0.5% solution) WSR N-60K 2,000,0002,000-4,000 (2% solution) PEO-15Z 3,300,000-3,800,000 130-250 (0.5%solution) WSR-301, 4,000,000 1,650-5,500 (1% solution) UCARFLOC Polymer300 PEO-18Z 4,300,000-4,800,000 250-430 (0.5% solution) WSR 5,000,0005,500-7,500 (1% solution) Coagulant, UCARFLOC Polymer 302 WSR-303,7,000,000 7,500-10,000 (1% solution) UCARFLOC Polymer 304 PEO-276,000,000-8,000,000 600-800 (0.5% solution) WSR-308, 8,000,00010,000-15,000 (1% solution) UCARFLOC Polymer 309

In general, any PEO material described herein or any known PEO havingthe characteristics of a PEO material as described herein can be used.

In one embodiment, the term “PEO Grade 1” is taken to mean apolyethylene oxide with a solution viscosity in the range of 12-8800mPa·s at 25° C. in a 5% solution or approximate molecular weight rangefrom 100,000-600,000. Examples of Grade 1 PEOs are listed in the tableabove and include POLYOX WSR N-10, WSR N-80, WSR N-750, WSR N-3000, WSRN-205 or equivalents thereof.

In one embodiment, the term “PEO Grade 2” is taken to mean apolyethylene oxide with a solution viscosity in the range of 8800 mpa·sat 25° C. in a 5% solution to 4000 mPa·s at 25° C. in a 2% solution orapproximate molecular weight range from 900,000-2,000,000. Examples ofGrade 2 PEOs are listed in the table above and include POLYOX WSRN-1105, WSR N-12K, WSR N-60, or equivalents thereof.

In one embodiment, the term “PEO Grade 3” is taken to mean apolyethylene oxide with a solution viscosity in the range of 1650-15,000mPa·s at 25° C. in a 1% solution or approximate molecular weight rangefrom 4,000,000-8,000,000. Examples of Grade 3 PEOs are listed in thetable above and include POLYOX WSR 301, WSR Coagulant, WSR 303, WSR 308,or equivalents thereof.

PEO Grade 1, PEO Grade 2 and/or PEO Grade 3 can occur in the drugreservoir layer, the inert backing layer or both layers. In theembodiment wherein a particular grade of PEO occurs in the reservoirlayer and the inert backing layer, that grade of PEO is independentlyselected at each occurrence from its respective definition. In otherwords, if PEO Grade 1 occurs in the reservoir layer and the backinglayer, then it will be selected at each occurrence from theabove-specified group for PEO Grade 1. Likewise for PEO Grade 2 and PEOGrade 3.

When three grades of PEO are included in the same layer, PEO Grade 3 hasa higher viscosity than PEO Grade 2, which has a higher viscosity thanPEO Grade 1. When two grades of PEO are included in the sameformulation, there are several possible combinations: a) PEO Grade 3+PEOGrade 2, wherein PEO Grade 3 has a higher viscosity than PEO Grade 2; b)PEO Grade 3+PEO Grade 1, wherein PEO Grade 3 has a higher viscosity thanPEO Grade 1; and c) PEO Grade 2+PEO Grade 1, wherein PEO Grade 2 has ahigher viscosity than PEO Grade 1.

When three different grades of PEO are present, the amount of eachranges from 5 to 50% by wt. of the layer. The total amount of PEOpresent generally ranges from about 10% to about 70%, about 20% to about70%, about 30% to about 70%, or about 40% to about 70% by wt. of thereservoir layer. Some embodiments of the reservoir layer include thosewherein the total amount of PEO is about 64%, 43.64%, 61.5%, 59%, 62.5%,63%, 65.82%, 60.82% by wt. of the reservoir layer.

The total amount of PEO present generally ranges from 0% to about 60%,about 10% to about 60%, about 20% to about 60% or about 40% to about 60%by wt. of the backing layer. Some embodiments of the backing layerinclude those wherein the total amount of PEO is about 10%, 35%, 50%,54%, 56%, 58% by weight of the backing layer.

In some embodiments, the amount of PEO Grade 1 ranges from 5 to 50% bywt. of the layer, such as 5%, 10%, 26.85%, 27.9%, 23.67%, 32.9%, 36.01%,34%, 38.16%, 33.86% of the layer; the amount of PEO Grade 2 ranges from5 to 50% by wt. of the layer, such as 5%, 22.18%, 21.16%, 26.16%,20.36%, 28.64%, 27%, 30.35%, 14.96%, 15.91%, 18.36%, 18.86%, 19.36%,7.5% of the layer; and the amount of PEO Grade 3 ranges from 5 to 50% bywt. of the layer, such as 13.79%, 16.29%, 16.79%, 17.44%, 19.1%, 18%,20.24%, 29.93%, 31.83%, 36.5%, 45% wt. of the layer.

When any type or class of material is present in both the reservoir andthe backing layer, it will be independently selected at each occurrencefrom the list of suitable materials described herein or known to theartisan in the field of pharmaceutics. For example, if PEO is present inboth the reservoir layer and the backing layer, the grade or grades ofPEO used in reservoir layer will be selected at each occurrenceindependently of the grade or grades of PEO used in the backing layer.

Suitable thermal binders that may or may not require a plasticizerinclude, for example, Eudragit™ RS PO, Eudragit™ S100, Kollidon SR(poly(vinyl acetate)-co-poly(vinylpyrrolidone) copolymer), HPC(hydroxypropylcellulose), cellulose acetate butyrate,poly(vinylpyrrolidone) (PVP), poly(ethylene glycol) (PEG), poly(ethyleneoxide) (PEO), poly(vinyl alcohol) (PVA), hydroxypropyl methylcellulose(HPMC), ethylcellulose (EC), hydroxyethylcellulose (HEC), sodiumcarboxymethyl-cellulose (CMC), dimethylaminoethylmethacrylate-methacrylic acid ester copolymer,ethylacrylate-methylmethacrylate copolymer (GA-MMA), C-5 or 60 SH-50(Shin-Etsu Chemical Corp.), cellulose acetate phthalate (CAP), celluloseacetate trimelletate (CAT), polyesters (shellac), waxes (carnauba wax,beeswax), poly(vinyl acetate) phthalate (PVAP),hydroxypropylmethylcellulose phthalate (HPMCP), poly(methacrylateethylacrylate) (1:1) copolymer (MA-EA), poly(methacrylatemethylmethacrylate) (1:1) copolymer (MA-MMA), poly(methacrylatemethylmethacrylate) (1:2) copolymer, Eudragit™ L100 (MA-EA, 1:1),Eudragit™ L-100-55 (MA-EA, 1:1), hydroxypropylmethylcellulose acetatesuccinate (HPMCAS), Coateric™ (PVAP), polycaprolactone, starches,pectins; polysaccharides such as cellulose, tragacanth, gum arabic, guargum, sugars and xanthan gum.

Some of the above-noted binders are bioadhesive alkaline thermoplasticpolymers. The matrix of the invention can include a combination ofmaterials, some of which are not alkaline, not bioadhesive, or notthermoplastic. It is only important that the matrix (e.g., the excipientmixture) retain its bioadhesive thermoplastic nature prior to hot-meltextrusion and retain its bioadhesive nature after hot-melt extrusion.

Other polymeric materials that can be included in the matrix includecellulosic polymers including HPMC, HPC, methylcellulose; polyvinylalcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate andother polymers approved for pharmaceutical use known to those ofordinary skill in the art.

The alkaline bioadhesive thermoplastic matrix can further comprise othermaterials, in particular other polymers such as KLUCEL(hydroxypropylcellulose), CARBOPOL, POLYCARBOPHIL GANTREZ, POLOXAMER,and combinations thereof. The product literature for CARBOPOL® indicatesthat aqueous solutions containing it have a pH in the range of 2.5-4.0,meaning it is an acidic polymer and not considered an alkaline polymer;however, it is a bioadhesive polymer. GANTREZ® is a copolymer of methylvinyl ether and maleic anhydride, and its solution pH will depend uponthe form in which it is provided. GANTREZ® MS is a mixed calcium andsodium salt of the polymer having a solution pH between 5.5-7.0.GANTREZ® is a bioadhesive polymer but not a thermoplastic polymer. Theproduct literature for POLYCARBOPHIL®, high molecular weight,cross-linked, acrylic acid-based polymers, indicates that aqueoussolutions containing it have a pH less than 4.0, meaning it is an acidicpolymer and not considered an alkaline polymer; however, it is abioadhesive polymer. POLOXAMER® 407 is a block copolymer of ethyleneglycol and propylene glycol and according to the product literature ithas a solution pH of 6.0-7.4. POLOXAMER® is not considered a bioadhesivepolymer and it is not a thermoplastic polymer.

An extrudate composed of PEO and POLOXAMER can form a homogeneouspolymer matrix when melt extruded at 100° C. Compositions furthercomprising HPMC, PVA, or SLS can be made.

The matrix or excipient mixture can contain one or more bioadhesivepolymers, one or more thermoplastic polymers and/or one or more alkalinepolymers. In one embodiment, the alkaline polymer is also thebioadhesive polymer. In another embodiment, the alkaline polymer is alsothe thermoplastic polymer. In still another embodiment, the bioadhesivepolymer is the thermoplastic polymer. Yet another embodiment includes analkaline polymer that is a bioadhesive polymer and a thermoplasticpolymer, wherein, in other words, a single polymer is bioadhesive,thermoplastic and alkaline prior to hot melt extrusion. Examples of suchpolymers include polyethylene oxide, hydroxypropylcellulose,hydroxyethylcellulose, hydroxypropyl methylcellulose, povidone andothers known to one of ordinary skill in the art.

The hot-melt extrusion equipment is typically a single or twin-screwapparatus, but can be composed of more than two screw elements. Atypical hot-melt extrusion apparatus contains a mixing/conveying zone, aheating/melting zone, and a pumping zone in succession up to theorifice. In the mixing/conveying zone, the powder blends are mixed andaggregates are reduced to primary particles by the shear force betweenthe screw elements and the barrel. In the heating/melting zone, thetemperature is at or above the melting point or glass transitiontemperature of the thermal binder or binders in the blend such that theconveying solids become molten as they pass through the zone. A thermalbinder in this context describes an inert excipient, typically apolymer, that is sufficiently solid at ambient temperature, but becomesmolten, softened or semi-liquid when exposed to elevated heat orpressure. The thermal binder acts as the matrix in which the active oractives and other functional ingredients are dispersed, or the adhesivewith which they are bound such that a continuous composite is formed atthe outlet orifice. Once in a molten state, the homogenized blend ispumped to the orifice through another heating zone that maintains themolten state of the blend. At the orifice, the molten blend can beformed into strands, cylinders or films. The extrudate that exits isthen solidified typically by an air-cooling cooling process. Theextrudate can be a single layer or it can be a coextruded laminate or abi-layered, tri-layered or multi-layered laminate formed by laminatingtwo or more layers together. Once solidified, the extrudate may then befurther processed to form pellets, spheres, fine powder, tablets, andthe like. An example of a single screw apparatus similar to thedescription above is the Randcastle Taskmaster, model 1 inch, 36:1.

Temperature is an important process variable to consider for thehot-melt extrusion. The composition can be HME at any temperaturedesired provided it does not result in excessive degradation of thecomposition or any of it components.

Other process variables such as feed rate and screw speed are optimizedto provide adequate shear and mixing. The effect of feed rate and screwspeed on such dependent variables as the level of shear and mixinginside the extruder depends heavily on the design of the equipment andnamely the screw elements. Generally, increasing the screw speed willincrease the shear forces between the screw element and the barrel wall,thereby allowing for more rigorous mixing and a greater extent ofparticle disaggregation. Decreasing the feed rate (non-flood feeding)will generally allow for more complete mixing and particledisaggregation due a reduction in the amount of material within theextruder. Reducing the amount of material will in turn also increase theshear forces the material is subjected to due to a decrease in theeffective channel depth.

It is also important to consider the ways in which the components of aformulation are fed to the extruder. One method is to pre-blend allformulation components before being fed to the extruder. This can bedone by any traditional mixing or blending technique. Alternatively,formulation components may be fed individually if done simultaneously,and given that there is adequate mixing of the formulation components inthe mixing/conveying zone of the extruder. For example, the drug ismixed with the excipient composition after formation of the excipientcomposition. The blend is then hot-melt extruded. Furthermore,components other than the base polymers may also be fed downstream ofthe initial feed port to reduce their residence time in the extrudergiven that there is adequate mixing of the formulation components beforeand in the last mixing zone. For example, an excipient blend may be fedat the initial feed port and a heat sensitive component may be fed priorto the last zone to minimize the time of heat exposure. Additionally, asolid non-melting component that significantly increases the meltviscosity may be fed downstream to reduce the amount of energy requiredto rotate the extruder screw.

The excipient mixture of the invention can be prepared by a variety ofdifferent methods. A key aspect to its preparation is contact of theacidic component with the bioadhesive alkaline thermoplastic polymer.One particular method is wet or dry granulation. In one embodiment, theexcipient mixture is prepared by wet granulating the bioadhesivealkaline thermoplastic polymer and the acidic component, and optionallyone or more other excipients, in the presence of an aqueous medium. Theexcipient mixture is optionally dried after wet granulation. Therefore,the dry or wet excipient mixture is mixed with drug, and optionally oneor more other excipients, to form a blend that is then hot-meltextruded. The aqueous medium can be added in portions or in a bolus. Inone embodiment, the alkaline polymer and the acidic polymer are wetgranulated and then a second bioadhesive polymer is added to thegranulate to prepare the excipient mixture.

One embodiment of the invention requires pre-formation of the excipientmixture prior to mixing with the alkaline labile drug. Other embodimentsrequire formation of the excipient composition by wet granulation withan aqueous liquid, wherein the aqueous liquid optionally comprisesalcohol.

The HME composition of the invention is made according to a process asdescribed herein. Exemplary formulations and processes for theirpreparation are detailed in the examples below.

The monolithic matrix of FIG. 1 is made by hot-melt extruding a blendcomprising an excipient composition and an alkaline labile drug. Generalmethods for hot-melt extrusion are detailed herein and in Example 1.

The advantages of the present process of the invention can beexemplified by evaluation of hot-melt extruded compositions containingtestosterone as the exemplary alkaline labile drug. The compositionswere prepared as described herein. Various processing variables wereevaluation to determine their influence upon the stability of the drugto hot-melt extrusion conditions.

Testosterone obtained commercially (for example, from Diosynth aDivision of Akzo Nobel, Arnhem, The Netherlands) already includes or caninclude a number of different impurities such as6-beta-hydroxytestosterone, 4-Androsten-16-alpha-ol-3,17-dione,Androstenedione, Epi-testosterone, which impurities are present invarying amounts. Some of these impurities are formed by virtue of thesynthetic process to prepare testosterone and others are formed due todegradation of the testosterone. During HME of a hot-melt extrudablealkaline thermoplastic matrix containing testosterone, the drug mightundergo degradation thereby producing new degradants or increasing theamounts of degradants already present.

The influence of the order of mixing of formulation components upon thestability of testosterone toward degradation during HME was evaluated.In Lot A, all of the formulation components were mixed (blended,granulated or slugged) in dry form to form a blend, which wassubsequently extruded. In Lot B, all of the formulation components weremixed in the presence of a liquid to form a wet granulate, that wasoptionally dried prior to HME.

Formulations made according to the process of the invention, however,demonstrated a significant reduction in the extent of testosteronedegradation occurring during HME. Prior to addition of an acidiccomponent, the thermoplastic bioadhesive matrix (or polymer) has asolution pH greater than 7 or ranging from about pH 8 to about pH 10.Following addition of the acidic component to the matrix, the excipientmixture has a solution pH of 7 or less or about pH 2.5 to pH 7.Exemplary lots of the excipient mixture were made according to theinvention. In Lot C, the alkaline thermoplastic matrix-forming materialwas dry granulated with the acidic component, and optionally one or moreother excipients, to form an excipient mixture having a solution pH(when dissolved) of about 7 or less or less than the pH wheretestosterone degrades during HME (See Example 1). The excipient mixturewas then mixed with testosterone and optionally other excipients to forma uniform blend (See Example 2) that is hot-melt extruded. In Lot D, thealkaline thermoplastic matrix-forming material was wet granulated withthe acidic component, and optionally one or more other excipients, toform an excipient mixture having a solution pH (when dissolved) of about7 or less or less than the pH where testosterone degrades during HME(See Example 1). The excipient mixture was then mixed with testosteroneand optionally other excipients to form a uniform blend (See Example 2)that is hot-melt extruded. Accordingly, HME compositions preparedaccording to the invention comprise lower amounts of impurities than dosimilar compositions comprising the same components but made withoutpreformation of an excipient mixture.

Total Unknown 6B-Hydroxy- 4-Androsten-16- Epi- Impurities testosteronealpha-ol-3,17- Testosterone^(b) Lot No. (%) (%) dione (%) (%) A0.20-4.50 0.05-1.50 0.05-1.50 0.00-1.50 B 0.20-4.50 0.05-1.50 0.05-1.500.00-1.50 C 0.00-2.00 0.00-0.50 0.00-0.50 0.00-0.50 D 0.00-2.000.00-0.50 0.00-0.50 0.00-0.50 ^(b)Epi-testosterone (cis-testosterone) isa concomitant component of testosterone (Per USP<1086>) Concomitantcomponents are characteristics of many bulk pharmaceutical chemicals andare NOT considered to be degradants.

The influence of having more than one type of acidic component upon thestability of testosterone to degradation during HME was evaluated. Lot56 incorporated citric acid as a secondary acidifier and butylatedhydroxytoluene as an antioxidant in place of Vitamin E succinate. Thelot was prepared by wet granulating the PolyOx and Poloxamer with 5%water under high shear. Carbopol was added and blended until uniform.Testosterone and the remaining ingredients were added and blended underhigh shear. The blend was extruded as a monolayer film using theRandcastle at 135° C. and 145° C. The moisture content of the blendprior to extrusion was 3.1%. Following extrusion, the film was cut intounit dose. Composites of 10 doses were analyzed for impurities induplicate. The table below includes the results.

Total Lot No./ Unknown 6B-Hydroxy- 4-Androsten-16- Epi- Temp. Impuritiestestosterone alpha-ol-3,17- Testosterone^(b) (° C.) (%) (%) dione (%)(%) No. 56 1.2 ND ND ND 135° C. No. 56 1.1 ND ND ND 145° C. ND denotesbelow the limit of quantitation using the HPLC method detailed herein.In this case, ND means less than 0.1% by wt.

In Lot 61 the antioxidant content was increased to 4% by wt. and thePoloxamer content was increased to 6% by wt. The blend was wetgranulated with water at 5% and extruded using the Randcastle at 135° C.Degradant levels were determined by HPLC and results are included in thetable above. The Poloxamer content was increased to 7.5% in Lot 62 andto 9% in Lot 63. The blends were wet granulated with water at 5% andextruded using the Randcastle at 135° C.

The influence of HME temperature upon degradation of testosterone wasevaluated. A HME composition was prepared by wet granulating PolyOx andPoloxamer with water under high shear. Carbopol was added and blendeduntil uniform. Testosterone and the remaining ingredients were added andblended under high shear. These blends were extruded as a monolayer filmusing the Randcastle at 135° C. or 145° C. The moisture content of theblend prior to extrusion was 3.1%. The purity profile of the resultingextrudates was determined. The table below indicates the results.

Total Unknown 6B-Hydroxy- 4-Androsten-16- Epi- Temp Impuritiestestosterone alpha-ol-3,17- Testosterone^(b) (° C.) (%) (%) dione (%)(%) 135 0.1 ND ND ND 145 0.4 0.15 ND ND

The influence of wet granulation technique (water addition rate,acidification time and water content) on testosterone stability wasinvestigated. The rate of water addition was studied by applying a“BOLUS” loading versus “SERIAL” addition (sequential addition ofportions). One lot was prepared using the bolus technique in which theentire water loading (5% based upon solids) was added in one step to thePolyOx, Poloxamer and Carbopol polymers under high shear. Another lotwas prepared by the serial technique in which the water and Carbopolloadings were incorporated into the PolyOx and Poloxamer polymers in 4separate steps. The results indicate a slightly lower degree ofdegradant formation when the granulation liquid is added as a bolusloading.

The effect of the quantity of water, used as the liquid medium duringwet granulation, upon drug stability was investigated. One lot wasprepared using the bolus technique with 7.5% water loading, which is ahigher water loading. A reduction in major impurities was observed usinghigher water loading. A water loading of up to 98% can be used providedthe extruder is equipped to handle the increased amounts of steam formedusing feed mixtures having high water content.

The influence that use of a hydroalcoholic granulation solution duringgranulation has upon drug stability was studied. In one lot, a 50:50water/ethanol solution (10% based upon solids) was used to wet granulatethe polymers. The resultant granules were dried at 60° C. to an LOD(loss on drying) of less than 3.1% prior to further processing. A lowerconcentration of degradants was present in the HME composition whenusing the hydroalcoholic granulation solution as compared to use of justwater as the granulation solution. The ratio of water to water misciblesolvent in the granulation solution can range from 5:95 to 95:5.

Total Granu- Unknown 6B-Hydroxy- 4-Androsten-16- Epi- lation Impuritiestestosterone alpha-ol-3,17- Testosterone^(b) Fluid (%) (%) dione (%) (%)Water 0.50-1.00 0.10-0.50 0.10-0.50 0.00-0.50 Aqueous 0.00-0.750.00-0.20 0.00-0.20 0.00-0.50 Ethanol

Formulations providing an extended release of drug can be made. Twoformulations were prepared using higher Carbopol loads in which thetarget film thickness was 1.50 mm. These formulations were prepared bythe hydroalcoholic wet granulation technique in which the Vitamin E andVitamin E Succinate were emulsified with the Poloxamer. The in vitrodissolution profiles are presented in FIGS. 4 a and 4 b. Theformulations differed in the amount of CARBOPOL polymer present: 12.5%(FIG. 4 a); 15% (FIG. 4 b). It can be concluded that increasing the dosethickness (increasing the thickness of the drug-containing compositionor layer) and increasing the Carbopol content in the formulation retardsthe in vitro dissolution rate. The thickness of the reservoir layer canrange from about 0.01 to about 20 mm or otherwise be manufactured in anysize adapted for a particular purpose.

The effectiveness of an acidic component as a neutralizer of thealkaline thermoplastic matrix may vary. As a result, its performance instabilization of an alkaline labile drug should be evaluated bypreparing hot-melt extruded compositions, using a procedure describedherein, containing varying amounts of the acidic component, and similaramounts of all other components. The HME compositions are then analyzed,such as by HPLC, to determine the differences in their purity profiles.The HME composition containing the lowest comparative amount ofimpurities is the better composition. In a similar manner, various HMEcompositions containing the same amount of different acidic componentscan be prepared and analyzed as described herein. The acidic componentresulting in a HME composition having the least amount of impurities isthe better acidic component. For example, POLYOX (PEO) polymers containresidual calcium salts from the catalyst during synthesis. A series ofexperiments was conducted using hydrochloric acid and phosphoric acid toneutralize these alkaline materials. The acidic component was added inliquid form to the granulation mass or the granulation liquid medium. Aformulation as described herein was prepared but was wet granulated witheither 50 mM hydrochloric Acid or 100 mM Phosphoric Acid. Twenty doseswere sampled from each lot at the beginning, middle and end of theextrusion run. Composites of 10 doses were analyzed for impurities induplicate. Major impurities were not identified in the samplesneutralized with hydrochloric acid. Small quantities of the6B-Hydroxy-testosterone were detected in the phosphoric acid sample. Itwas determined that HCl provided better stabilization of testosteronethan does H₃PO₄ even though both were acceptable under the evaluationcriteria.

The total acidic component is present in an amount sufficient toneutralize alkaline species present in the matrix. In other words, theacidic component is added in an amount sufficient to achieve a pH withinthe desired range (e.g., 7 or less or less than the pH which results indegradation of the alkaline labile species). In one embodiment, thetotal molar concentration of acidic component (or of total acidicgroups) equals or exceeds the molar concentration of total alkalinegroups present in the excipient composition. An acidic component canhave 1, 2 or more moles of acidic groups per mole of acidic component.

Optionally, no wet granulation is required. In this embodiment, allmaterials to be added to a formulation are blended and then hot-meltextruded. This process, however, is only suitable when water solubleacidic components are used, as non-water soluble acidic components, suchas CARBOPOL®, do not stabilize the film as well in this type of process.This because CARBOPOL® requires water for hydration in order to exertits acidic property. One way to overcome this disadvantage is to wet thenon-water soluble acidic component prior to granulation with thebioadhesive alkaline thermoplastic polymer and extending the granulationtime sufficiently to permit interaction of the non-water soluble acidiccomponent with the bioadhesive alkaline thermoplastic polymer to form aneutral or moderately acidic excipient mixture.

As used herein, the term “acidic component” or “acidifying agent” meansone or more acidic polymers (e.g. Carbopol®, Polycarbophil, polyacrylicacid), one or more inorganic acids (e.g. a mineral acid, (phosphoricacid, boric acid, hydrochloric acid, nitric acid, sulfuric acid,hydrobromic acid), one or more organic acids (non-polymeric carboxylicacid such as acetic acid, citric acid, tartaric acid, turmeric acid,succinic acid, amino acid, alpha-hydroxyl acid, ascorbic or adipicacid), or a combination thereof. An acidic component also includes thesalt form or buffer of an acid, wherein the salt has solution pH of lessthan 7 or less than 6 when dissolved in water. The above-listed acidiccomponents are merely illustrative and non-limiting. Any acidiccomponent having a pKa of less than 7 or less than 6 would be suitablefor use in the present invention. Specific embodiments include thosewherein the acidic component is selected from the group consisting of:hydrochloric acid, phosphoric acid, citric acid and a combinationthereof.

An acidic component can be a combination of an acidic polymer and anorganic acid, an acidic polymer and an inorganic acid, or an inorganicacid and an organic acid. An acidic component may also be a combinationor two or more acidic polymers, two or more inorganic acids, or two ormore organic acids.

Some lots incorporated citric acid as a secondary acidifier without anantioxidant. The blend was wet granulated with water at 5% and extrudedusing the Randcastle at 135° C. *Degradants were not detected in thesamples, although a peak (likely citric acid) eluted between the majorimpurities.

Total Lot No./ Unknown 6B-Hydroxy- 4-Androsten-16- Epi- Temp. Impuritiestestosterone alpha-ol-3,17- Testosterone^(b) (° C.) (%)* (%) dione (%)(%) No. 56 2.90 ND ND ND 135° C. No. 61 0.95 0.1 ND ND 135° C.

The solid dosage formulations of the invention can assume any shape orform known in the art of pharmaceutical sciences. The dosage form can bea sphere, tablet, bar, plate, paraboloid of revolution, ellipsoid ofrevolution or other one known to those of ordinary skill in the art. Thesolid dosage form can also include surface markings, cuttings, grooves,letters and/or numerals for the purposes of decoration, identificationand/or other purposes.

The matrix and/or the additional functional excipients may be formulatedso as to provide a predetermined approximate release profile underpredetermined conditions. The drug can be released according to animmediate, rapid, sustained, controlled, slow, or extended, andoptionally delayed, or targeted drug release profile.

The pharmaceutical composition may deliver one or more active agents inan extended release manner, and mechanisms employed for such deliverycan include active agent release that is pH-dependent or pH-independent;diffusion or dissolution controlled; erosion controlled; pseudo-zeroorder (approximates zero-order release), zero-order, pseudo-first order(approximates first-order release), or first-order; or slow, delayed,timed or sustained release or otherwise controlled release. The releaseprofile for the active agent can also be sigmoidal in shape, wherein therelease profile comprises an initial slow release rate, followed by amiddle faster release rate and a final slow release rate of activeagent.

As used herein, the term “extended release” profile assumes thedefinition as widely recognized in the art of pharmaceutical sciences.An extended release dosage form will release drug at substantiallyconstant rate over an extended period of time or a substantiallyconstant amount of drug will be released incrementally over an extendedperiod of time. An extended release tablet generally effects at least atwo-fold reduction in dosing frequency as compared to the drug presentedin a conventional dosage form (e.g., a solution or rapid releasingconventional solid dosage forms).

By “controlled release” is meant a release of an active agent to anenvironment over a period of about eight hours up to about 12 hours, 16hours, 18 hours, 20 hours, a day, or more than a day. By “sustainedrelease” is meant an extended release of an active agent to maintain aconstant drug level in the blood or target tissue of a subject to whichthe device is administered. The term “controlled release”, as regards todrug release, includes the terms “extended release”, “prolongedrelease”, “sustained release”, or “slow release”, as these terms areused in the pharmaceutical sciences. A controlled release can beginwithin a few minutes after administration or after expiration of a delayperiod (lag time) after administration.

A slow release dosage form is one that provides a slow rate of releaseof drug so that drug is released slowly and approximately continuouslyover a period of 3 hr, 6 hr, 12 hr, 18 hr, a day, 2 or more days, aweek, or 2 or more weeks, for example.

A timed release dosage form is one that begins to release drug after apredetermined period of time as measured from the moment of initialexposure to the environment of use.

A targeted release dosage form generally refers to a dosage form that isdesigned to deliver drug to a particular portion of the dermis or mucosaof a subject.

By “delayed release” is meant that initial release of drug occurs afterexpiration of an approximate delay (or lag) period. For example, ifrelease of drug from an extended release composition is delayed twohours, then release of drug from begins at about two hours afteradministration of the composition, or dosage form, to a subject. Ingeneral, a delayed release is opposite an immediate release, whereinrelease of drug begins after no more than a few minutes afteradministration. Accordingly, the drug release profile from a particularcomposition can be a delayed-extended release. A “delayed-extended”release profile is one wherein extended release of drug begins afterexpiration of an initial delay period.

A pseudo-first order release profile is one that approximates a firstorder release profile. A first order release profile characterizes therelease profile of a dosage form that releases a constant percentage ofan initial drug charge per unit time.

A pseudo-zero order release profile is one that approximates azero-order release profile. A zero-order release profile characterizesthe release profile of a dosage form that releases a constant amount ofdrug per unit time.

FIG. 2 depicts a conceptual cross-sectional front elevation of anexemplary bi-layered hot-melt extruded composition (3) (a laminate)comprising a drug reservoir layer (2) and a backing layer (4). The drugreservoir is a bioadhesive layer comprising an alkaline labile drug,acidic component, and bioadhesive alkaline thermoplastic polymer. Thebacking layer is non-bioadhesive and generally more hydrophobic than thereservoir layer.

The hydrophobic composition of the backing layer generally comprises ahydrophobic non-bioadhesive thermoplastic matrix. Suitable materialsthat can be used in preparing the matrix of the backing layer include,by way of example and without limitation, EUDRAGIT, ethylcellulose,polyethylene, cellulose acetate butyrate, cellulose acetate phthalate,wax, polyvinyl alcohol, polyvinyl acetate phthalate, polyester, shellac,other materials recognized in the chemical arts as having similarphysical properties, or a combination thereof. The backing layer can beextruded as described herein or it can be a prefabricated layer that issubsequently laminated to the reservoir layer. Alternatively, thebacking layer can be cast onto the drug-containing layer. In oneembodiment, the backing layer is impermeable to aqueous medium and drug.Non-limiting exemplary materials suitable for this type of backing layerinclude ethylcellulose, EUDRAGIT RS, wax, other materials recognized inthe chemical arts as having similar physical properties, or acombination thereof. In another embodiment, it is semipermeable, meaningit is impermeable to drug and permeable to aqueous medium. Non-limitingexemplary materials suitable for this type of backing layer include PEOand ethylcellulose, PEO and EUDRAGIT RS, cellulose acetate and itsderivatives, other materials recognized in the chemical arts as havingsimilar physical properties, or a combination thereof. In still anotherembodiment, it is permeable to aqueous medium and drug. Non-limitingexemplary materials suitable for this type of backing layer include PEOand EUGRAGIT E, other materials recognized in the chemical arts ashaving similar physical properties, or a combination thereof.

The backing layer is typically inert, meaning it does not contain atherapeutically active agent. However, the backing layer can optionallyinclude a therapeutically active agent, and its active agent can be thesame as or different than the one in the reservoir layer.

An exemplary backing layer was made according to the examples below. Inone embodiment, the hydrophobic composition of the backing layer isextruded separately from the hydrophilic composition of the reservoirlayer. In another embodiment, the hydrophobic composition of the backinglayer is coextruded with the hydrophilic composition of the reservoirlayer. In one embodiment, the backing layer and reservoir layers areextruded and shortly thereafter heat-laminated, solvent-laminated, oradhesive-laminated together during manufacture. In another embodiment,the backing layer and the reservoir layer are extruded separately andsubsequently heat-laminated, solvent-laminated or adhesive-laminatedtogether. In another embodiment, one layer is extruded onto the otherlayer which has been preformed, such as by extrusion or casting.

The step of heat-catalyzed lamination is conducted by passing thebacking layer and reservoir layer in contact with each othersimultaneously through a laminator that applies pressure and optionallyheat to the opposing layers. If the layers are sufficiently hot prior tolamination, they need not be heated again when placed in the laminator.If the layers are not sufficiently hot prior to lamination to permitsuitable lamination, then they are heated just prior to and/or duringlamination. The heat source can be located within or external to thelaminator. The layers will generally be heated to about 100-170° C. orat least about 60° C. prior to and/or during lamination. The temperaturefor lamination will be below the temperature at which a layer degrades.

Lamination can also be achieved without heat by applying a fine mist ofwater or other suitable solvent or plasticizer two one or both of theopposing layers immediately prior to combining under pressure. Thissolvent lamination process is suitable when the reservoir layer and thebacking layer each comprise a solvent-activated or plasticizer-activatedadhesive material such as PEO.

The laminator can be a set of opposing rollers driven by one or twomotors. The laminator will apply pressure to both layers during thelamination step. The contact pressure will generally be at least 40pounds per linear inch or in the range of about 40-600 pounds per linearinch. The laminator rollers will be sufficiently rigid to withstand theforces exerted. The rollers may be hollow and internally baffled toallow for the use of a heat transfer fluid. The rollers may be comprisedof a multiple metals and/or alloys providing suitable hardness and maycontain suitable coatings to provide adequate release of the heatedpolymer. Suitable coatings for the rollers include, for example,Teflon®, Titanium Nitride, Chrome, and other material(s) used in thepolymer industry for coating of heat laminators.

When the reservoir layer is adhesive-laminated to the backing layer, theadhesive is a material known in the field of polymers as suitable toadhering the two layers together. The specific adhesive will varyaccording to the chemical composition, chemical properties, and physicalproperties of the reservoir layer and the backing layer. A non-limitingexemplary adhesive comprises KLUCEL and EUDRAGIT E100. For example, abioadhesive reservoir layer comprising a hydrophilic HME matrix can beadhered to a non-bioadhesive backing layer comprising a hydrophobic HMEmatrix by applying an adhesive material at the interface between the twolayers and subsequently pressing the two layers together. Weight orpressure can be applied to the layers optionally followed by drying toremove solvent, if present, from the adhesive.

Since the backing layer can be intimate contact with the reservoirlayer, its pH might impact the stability of the drug in the reservoirlayer. Studies to investigate the pH (when placed in solution) of thebacking layer were conducted to eliminate the potential for drugdegradation at the interface between the backing layer and the reservoirlayer in a laminate composition. Such degradation may occur duringheat-catalyzed lamination or during storage of the laminate. The pH ofthe backing layer (made according to one of the examples below) wasdetermined to be 9.0 after dispersing 2 grams in 100 mL of purifiedwater. The pH of the suspension was determined after aliquots of citricacid monohydrate were added. Addition of 10 mg of citric acid reducedthe suspension pH to 4.6 and addition of 50 mg reduced the suspension pHto 3.4. A backing film formulation was prepared containing 1.0% citricacid. The citric acid monohydrate was dissolved in water (5% based onsolids) and wet granulated with the PolyOx polymers. The remainingmaterials were blended under high shear followed by granulation withdibutyl sebacate. The results indicate decreased degradation of drug inthe reservoir layer when the backing layer included an acidic componentin an amount sufficient to render the solution pH of the backing filmless than about 7 or less than the pH at which the alkaline labile drugdegrades.

The ratio of the thickness of the reservoir layer to the thickness ofthe backing layer can be varied as needed depending upon the performancedesired for the laminate. In one embodiment, the ratio ranges from about0.1:1 to about 5:1 or about 1:1 to 4:1.

When the backing layer and reservoir layer are laminated together byheat-catalyzed lamination, they will preferably have at least onepolymer in common. For example, if the reservoir layer contains PEO,then the backing layer could contain PEO.

Generally, the reservoir layer and the backing layer possess melt flowindices that are not too dissimilar if the layers are to be laminated byheat-catalyzed lamination in the absence of an adhesive between thelayers. This means their melt flow indices will fall within individualpredefined ranges and that those ranges overlap at least to somepredefined extent. For example, the melt flow index of the reservoirlayer can be within no more than 75% or within no more than 50% of themelt flow index of the backing layer. As used herein, the term melt flowindex is taken to mean the amount, in grams, of a resin which can beforced through a plastometer or rheometer (as defined in ASTM D1238) inten minutes at a given temperature and force.

FIG. 3 depicts a conceptual cross-sectional front elevation of anexemplary tri-layered hot-melt extruded composition (5) comprising adrug reservoir layer (2), a backing layer (4) and a release liner layer(6). The drug reservoir is a bioadhesive layer comprising an alkalinelabile drug, acidic component, and bioadhesive alkaline thermoplasticpolymer. The backing layer is non-bioadhesive and generally morehydrophobic than the reservoir layer.

The release liner layer temporarily adheres to the bioadhesive layerduring storage of the HME composition, and it is removable by handbefore administration of the HME composition to a subject. The releaselayer may or may not be coextruded with the other two layers.

Any release layer that can temporarily adhere to the reservoir layerwill be suitable for use according to the invention. Exemplarynon-limiting suitable release layers obtainable from commercial sourcesinclude DOW SARANEX™, DOW BLF, 3M CoTran and SCOTCHPAK, Delstar Stratexand Delnet.

The release layer is attached to the face of the reservoir layer that isopposite the backing layer such that the release layer and backing layeroppose one another. In other words, the reservoir layer is between therelease layer and the backing layer. The contact surface area of therelease layer can be the same size as or bigger than the correspondingcontact surface of the reservoir layer.

The matrix of the invention may also contain various functionalexcipients, such as: hydrophilic polymer, antioxidant,super-disintegrant, surfactant including amphiphilic molecules, wettingagent, stabilizing agent, retardant, thermal lubricant, colorant,solubilizer, chelating agent, similar functional excipient, orcombination thereof, and plasticizers including citrate esters,polyethylene glycols, PG, triacetin, diethylphthalate, castor oil, andothers known to those or ordinary skill in the art. Extruded materialmay also include an acidifying agent, adsorbent, alkalizing agent,buffering agent, colorant, flavorant, sweetening agent, diluent,opaquant, complexing agent, fragrance, preservative or a combinationthereof.

As used herein, the term “adsorbent” is intended to mean an agentcapable of holding other molecules onto its surface by physical orchemical (chemisorption) means. Such compounds include, by way ofexample and without limitation, powdered and activated charcoal andother materials known to one of ordinary skill in the art.

A buffering agent is used to resist change in pH upon dilution oraddition of acid or alkali. Such compounds include, by way of exampleand without limitation, potassium metaphosphate, potassium phosphate,monobasic sodium acetate and sodium citrate anhydrous and dihydrate,salts of inorganic or organic acids, salts of inorganic or organicbases, and others known to those of ordinary skill in the art.

As used herein, the term “alkalizing agent” is intended to mean acompound used to provide alkaline medium for product stability. Suchcompounds include, by way of example and without limitation, ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodiumbicarbonate, sodium hydroxide, triethanolamine, and trolamine and othersknown to those of ordinary skill in the art.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to solid (e.g., tablets) pharmaceutical preparations.Such compounds include, by way of example and without limitation, FD&CRed No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&CGreen No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide,red, other F.D. & C. dyes and natural coloring agents such as grape skinextract, beet red powder, beta-carotene, annato, carmine, turmeric,paprika, and other materials known to one of ordinary skill in the art.The amount of coloring agent used will vary as desired.

Exemplary chelating agents include EDTA, polycarboxylic acids,polyamines, derivatives thereof, and others known to those of ordinaryskill in the art.

Exemplary hydrophilic polymers which can be a primary or secondarypolymeric carrier that can be included in the composition includepoly(vinyl alcohol) (PVA), polyethylene-polypropylene glycol (e.g.POLOXAMER™), carbomer, polycarbophil, or chitosan. The “hydrophilicpolymers” of the present invention include one or more of hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, methylcellulose, natural gums such as gum guar,gum acacia, gum tragacanth, or gum xanthan, and povidone. “Hydrophilicpolymers” also include polyethylene oxide, sodium carboxymethycellulose,hydroxyethyl methyl cellulose, hydroxymethyl cellulose,carboxypolymethylene, polyethylene glycol, alginic acid, gelatin,polyvinyl alcohol, polyvinylpyrrolidones, polyacrylamides,polymethacrylamides, polyphosphazines, polyoxazolidines,poly(hydroxyalkylcarboxylic acids), carrageenate alginates, carbomer,ammonium alginate, sodium alginate, or mixtures thereof.

Exemplary hydrophobic polymers include alkylcelluloses, ethyl cellulose,Eudragit RS, waxes, polyesters, combinations thereof, and others knownto those of ordinary skill in the art.

Thermal lubricants include glyceryl monostearate, vitamin E succinate,glycerol monooleate, combinations thereof, and others known to those ofordinary skill in the art.

Solubilizers include cyclodextrins, povidone, combinations thereof, andothers known to those of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by oxidation due to the presence of oxygen free radicals orfree metals in the composition. Such compounds include, by way ofexample and without limitation, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, monothioglycerol, sodium ascorbate, sodium formaldehydesulfoxylate and sodium metabisulfite and others known to those ofordinary skill in the art. Other suitable antioxidants include, forexample, vitamin C, BHT, BHA, sodium bisulfite, vitamin E and itsderivatives, propyl gallate or a sulfite derivative.

As used herein, the term “disintegrant” is intended to mean a compoundused in solid dosage forms to promote the disruption of a solid mass(layer) into smaller particles that are more readily dispersed ordissolved. Exemplary disintegrants include, by way of example andwithout limitation, starches such as corn starch, potato starch,pre-gelatinized and modified starches thereof, sweeteners, clays,bentonite, microcrystalline cellulose (e.g., Avicel™),carboxymethylcellulose calcium, croscarmellose sodium, alginic acid,sodium alginate, cellulose polyacrilin potassium (e.g., Amberlite™),alginates, sodium starch glycolate, gums, agar, guar, locust bean,karaya, pectin, tragacanth, crospovidone and other materials known toone of ordinary skill in the art. A superdisintegrant is a rapidlyacting disintegrant. Exemplary superdisintegrants include crospovidoneand low substituted HPC.

Suitable surfactants include Polysorbate 80, sorbitan monooleate, sodiumlauryl sulfate or others. Soaps and synthetic detergents may be employedas surfactants. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts. Suitable detergents includecationic detergents, for example, dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether andmonoglyceride sulfates, and sulfosuccinates; nonionic detergents, forexample, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene)-block-poly(oxypropylene) copolymers; and amphotericdetergents, for example, alkyl β-aminopropionates and 2-alkylimidazolinequaternary ammonium salts; and mixtures thereof.

Wetting agent is an agent that decreases the surface tension of aliquid. Wetting agents would include alcohols, glycerin, proteins,peptides water miscible solvents such as glycols, hydrophilic polymersPolysorbate 80, sorbitan monooleate, sodium lauryl sulfate, fatty acidalkali metal, ammonium, and triethanolamine salts, dimethyl dialkylammonium halides, alkyl pyridinium halides, and alkylamine acetates;anionic detergents, for example, alkyl, aryl and olefin sulfonates,alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates;nonionic detergents, for example, fatty amine oxides, fatty acidalkanolamides, and poly(oxyethylene)-block-poly(oxypropylene)copolymers; and amphoteric detergents, for example, alkylβ-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; andmixtures thereof.

Retardants are agents that are insoluble or slightly soluble polymerswith a Tg above 45° C., more preferably above 50° C. before beingplasticized by other agents in the formulation including other polymersand other excipients needed for processing. The excipients includewaxes, acrylics, cellulosics, lipids, proteins, glycols, and the like.

A desiccant can be used to aid in storing a formulation according to theinvention. Suitable desiccants include sodium sulfate, calcium sulfate,magnesium sulfate, sodium hydroxide, sodium bicarbonate, clay,vermiculite, paper, activated alumina, zeolite, calcium chloride,molecular sieve, or anhydrous chemicals. In some cases a desiccant isneeded if the matrix materials or the drug are hygroscopic sincemoisture may affect the stability of the HME composition and/or drugtherein.

As used herein, the term “opaquant” is intended to mean a compound usedto render a composition opaque. It may be used alone or in combinationwith a colorant. Such compounds include, by way of example and withoutlimitation, titanium dioxide and other materials known to one ofordinary skill in the art.

Some of the materials listed herein may be too brittle or may have Tgvalues that are generally too high rendering them too difficult toextrude. The glass transition temperature is reduced upon the additionof a plasticizer. As used herein, the glass transition temperature istaken to mean the temperature at which a solid material softens or melts(or the glass transition temperature (Tg) is the temperature at which apolymer changes during the heat cycle from a brittle substance (glass)to a rubbery mass). Such materials can be combined with one or moreplasticizers to render them thermoformable. Plasticizers, such as lowmolecular weight PEG, generally broaden the average molecular weight ofa polymer in which they are included thereby lowering its glasstransition temperature or softening point. Plasticizers also generallyreduce the viscosity of a polymer. It is possible the plasticizer willimpart some particularly advantageous physical properties to the film ofthe invention.

Plasticizers useful in the invention can include, by way of example andwithout limitation, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin. Such plasticizers can alsoinclude ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, diethylene glycol, triethylene glycol, tetraethyleneglycol and other poly(ethylene glycol) compounds, monopropylene glycolmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate and allyl glycolate. All such plasticizers arecommercially available from sources such as Aldrich or Sigma ChemicalCo. It is also contemplated and within the scope of the invention, thata combination of plasticizers may be used in the present formulation.The PEG based plasticizers are available commercially or can be made bya variety of methods, such as disclosed in Poly(ethylene glycol)Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.;Plenum Press, NY) the disclosure of which is hereby incorporated byreference.

Preservatives include compounds used to prevent the growth ofmicroorganisms. Suitable preservatives include, by way of example andwithout limitation, benzalkonium chloride, benzethonium chloride, benzylalcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethylalcohol, phenylmercuric nitrate and thimerosal and others known to thoseof ordinary skill in the art.

As used herein, the term “flavorant” is intended to mean a compound usedto impart a pleasant flavor and often odor to a pharmaceuticalpreparation. Exemplary flavoring agents or flavorants include syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may also include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leafoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Other useful flavors include vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavors that have been found to be particularly useful includecommercially available orange, grape, cherry and bubble gum flavors andmixtures thereof. The amount of flavoring may depend on a number offactors, including the organoleptic effect desired. Flavors will bepresent in any amount as desired by those of ordinary skill in the art.Particularly preferred flavors are the grape and cherry flavors andcitrus flavors such as orange.

It should be understood, that compounds used in the art ofpharmaceutical formulation generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

The HME composition of the invention will include at least one activeagent when included in a dosage form. Generally an effective amount ofactive agent is included. By the term “effective amount”, it isunderstood that, with respect to, for example, pharmaceuticals, atherapeutically effective amount is contemplated. A therapeuticallyeffective amount is the amount or quantity of drug that is sufficient toelicit the required or desired therapeutic response, or in other words,the amount that is sufficient to elicit an appreciable biologicalresponse when administered to a patient.

The active agent can be present in its free acid, free base orpharmaceutically acceptable salt form. As used herein, “pharmaceuticallyacceptable salts” refer to derivatives of the disclosed compoundswherein the active agent is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of the drug. Thepharmaceutically acceptable salts include the conventional non-toxicsalts, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic,sulfamic, phosphoric, nitric and the like; and the salts prepared fromorganic acids such as amino acids, acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and other known to those ofordinary skill in the pharmaceutical sciences. Lists of suitable saltsare found in texts such as Remington's Pharmaceutical Sciences, 18th Ed.(Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, Pa., 1990);Remington: the Science and Practice of Pharmacy 19^(th) Ed. (Lippincott,Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3^(rd)Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999); thePharmaceutical Codex: Principles and Practice of Pharmaceutics 12^(th)Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The UnitedStates Pharmacopeia: The National Formulary (United States PharmacopeialConvention); and Goodman and Gilman's: the Pharmacological Basis ofTherapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill,1992), the disclosures of which are hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The alkaline-labile drug can be included in the HME composition incrystalline or amorphous form. It can be a salt, free-base, orfree-acid. It can be non-ionic, polar, apolar, cationic, or anionic. Itcan be present in hydrous or anhydrous form. The active agent can bepresent in its diastereomeric, isomeric, enantiomerically pure, racemic,hydrate, chelate, derivative, analog, or other common form.

Active agents include compounds (therapeutic compounds) forpharmaceutical use, such as human or veterinary use.

As used herein, the terms “therapeutic compound”, “therapeutic agent”,“active agent” and “drug” are used interchangeably, unless otherwisespecified. The process of the invention can be used to preparecomposition and dosage forms comprising essentially any one or moreactive agents. Active agents include physiological substances orpharmacological active substances that produce a systemic or localizedeffect or effects on animals and human beings.

A specific aspect of the invention includes one or more alkaline labileactive agents. An alkaline labile active agent is one that degradesunder alkaline conditions during processing and/or storage. Alkaline isdefined as a pH of greater than 7. For example, when a material beingtested is dissolved or dispersed in water, the liquid (water) will havea pH of greater than 7. An alkaline polymer is a polymer that forms asolution having a pH greater than 7 when the polymer is placed,dissolved and/or dispersed in water. Exemplary alkaline labile activeagents include one or more functional groups selected from the groupconsisting of an ester, amide, urea, acetal, ketal, carbamate,carbonate, lactone, lactam, halide, nitrate, phosphate, sulfate,sulfonate, phosphonate, imidate, imine, sulfide, hydroxide-reactive(hydroxide-unstable) functional group and amine reactive (amineunstable) functional group. By “hydroxide-reactive” or “hydroxideunstable” functional group is meant a functional group that reacts witha hydroxide moiety when placed in an alkaline medium. By“amine-reactive” or “amine unstable” functional group is meant afunctional group that reacts with a primary, secondary or tertiary aminemoiety when placed in an alkaline medium.

Particular alkaline labile drugs include, by way of example and withoutlimitation, testosterone, oxybutynin, morphine, fentanyl, aspirin,lansoprazole, omeprazole, pantoprazole, rabeprazole, Naltrexone,benzocaine, penicillin G, noradrenaline, isoprenaline, thiamine andatracurium.

Even though the invention is particularly suited for alkaline labiledrugs, drugs that are stable under alkaline conditions can also beemployed in the process and HME composition of the invention. Activeagents include compounds (therapeutic compounds) for pharmaceutical use,such as human or veterinary use. The active agent can be present in itsneutral, ionic, salt, basic, acidic, natural, synthetic, diastereomeric,isomeric, enantiomerically pure, racemic, hydrate, chelate, derivative,analog, or other common form.

Further therapeutic compounds which can be formulated into the presentcomposition also include an antibacterial substance, antihistamine(histamine receptor inhibitor), decongestant, anti-inflammatory agent,antiparasitic agent, antiviral agent, local anesthetic, antifungalagent, amoebicidal agent, trichomonocidal agent, analgesic agent,antiarthritic agent, antiasthmatic agent, anticoagulant agent,anticonvulsant agent, antidepressant agent, antidiabetic agent,antineoplastic agent, antipsychotic agent, neuroleptic agent,antihypertensive agent, muscle relaxant, depressant agent, hypnoticagent, sedative agent, psychic energizer, tranquilizer, antiparkinsonagent, muscle contractant, anti-microbial agent, antimalarial agent,hormonal agent, contraceptive agent, sympathomimetic agent, diureticagent, hypoglycemic agent, ophthalmic agent, anti-hypercholesterolemiaagent, anti-hypocholesterolemia agent, electrolyte, diagnostic agent,cardiovascular drug, vitamin, nutrient, nutritional agent, hematologicalagent, endocrine agent, metabolic agent, renal agent, genitourinaryagent, respiratory agent, central nervous system agent, gastrointestinalagent, anti-infective agent, biologic agent, immunological agent,dermatological agent, ophthalmic agent, and other type of therapeuticcompound known to those of ordinary skill in the pharmaceuticalsciences, and combinations thereof.

Exemplary nutrients and nutritional agents include as minerals, traceelements, amino acids, lipotropic agents, enzymes and chelating agents.Exemplary hematological agents include hematopoietic agents,antiplatelet agents, anticoagulants, coumarin and indandionederivatives, coagulants, thrombolytic agents, antisickling agents,hemorrheologic agents, antihemophilic agents, hemostatics, plasmaexpanders and hemin. Exemplary endocrine and metabolic agents includesex hormones, uterine-active agents, bisphosphonates, antidiabeticagents, glucose elevating agents, adrenocortical steroids, parathyroidhormone, thyroid drugs, growth hormones, posterior pituitary hormones,octreotide acetate, imiglucerase, calcitonin-salmon, sodiumphenylbutyrate, betaine anhydrous, cysteamine bitartrate, sodiumbenzoate and sodium phenylacetate, bromocriptine mesylate, cabergoline,agents for gout, and antidotes. Exemplary cardiovascular agents includenootropic agents, antiarrhythmic agents, calcium channel blockingagents, vasodilators, antiadrenergics/sympatholytics, renin angiotensinsystem antagonists, antihypertensive combinations, agents forpheochromocytoma, agents for hypertensive emergencies,antihyperlipidemic agents, antihyperlipidemic combination products,vasopressors used in shock, potassium removing resins, edetate disodium,cardioplegic solutions, agents for patent ductus arteriosus, andsclerosing agents. Exemplary renal and genitourinary agents includeinterstitial cystitis agents, cellulose sodium phosphate, anti-impotenceagents, acetohydroxamic acid (aha), genitourinary irrigants,cystine-depleting agents, urinary alkalinizers, urinary acidifiers,anticholinergics, urinary cholinergics, polymeric phosphate binders,vaginal preparations, and diuretics. Exemplary respiratory agentsinclude bronchodilators, leukotriene receptor antagonists, leukotrieneformation inhibitors, nasal decongestants, respiratory enzymes, lungsurfactants, antihistamines, normarcotic antitussives, and expectorants.Exemplary central nervous system agents include CNS stimulants, narcoticagonist analgesics, narcotic agonist-antagonist analgesics, centralanalgesics, acetaminophen, salicylates, normarcotic analgesics,nonsteroidal anti-inflammatory agents, agents for migraine,antiemetic/antivertigo agents, antianxiety agents, antidepressants,antipsychotic agents, cholinesterase inhibitors, nonbarbituratesedatives and hypnotics, nonprescription sleep aids, barbituratesedatives and hypnotics, general anesthetics, anticonvulsants, musclerelaxants, antiparkinson agents, adenosine phosphate, cholinergic musclestimulants, disulfuram, smoking deterrents, riluzole, hyaluronic acidderivatives, and botulinum toxins. Exemplary gastrointestinal agentsincluding H pylori agents, histamine H2 antagonists, proton pumpinhibitors, sucralfate, prostaglandins, antacids, gastrointestinalanticholinergics/antispasmodics, mesalamine, olsalazine sodium,balsalazide disodium, sulfasalazine, celecoxib, infliximab,esomeprazole, famotidine, lansoprazole, omeprazole, pantoprazole,rabeprazole, tegaserod maleate, laxatives, antidiarrheals,antiflatulents, lipase inhibitors, GI stimulants, digestive enzymes,gastric acidifiers, hydrocholeretics, gallstone solubilizing agents,mouth and throat products, systemic deodorizers, and anorectalpreparations. Exemplary anti-infective agents including penicillins,such as amoxicilin, cephalosporins and related antibiotics, carbapenem,monobactams, chloramphenicol, quinolones, fluoroquinolones,tetracyclines, macrolides, such as azithromycin, clarithromycin, and thelike, spectinomycin, streptogramins, vancomycin, oxalodinones,lincosamides, oral and parenteral aminoglycosides, colistimethatesodium, polymyxin B sulfate, bacitracin, metronidazole, sulfonamides,nitrofurans, methenamines, folate antagonists, antifungal agents, suchas fluconazole, voriconazole, and the like, antimalarial preparations,antituberculosis agents, amebicides, antiviral agents, antiretroviralagents, leprostatics, antiprotozoals, anthelmintics, and CDCanti-infective agents. Exemplary biologic and immunological agentsincluding immune globulins, monoclonal antibody agents, antivenins,agents for active immunization, allergenic extracts, immunologic agents,and antirheumatic agents. Exemplary antineoplastic agents includealkylating agents, antimetabolites, antimitotic agents,epipodophyllotoxins, antibiotics, hormones, enzymes,radiopharmaceuticals, platinum coordination complex, anthracenedione,substituted ureas, methylhydrazine derivatives, imidazotetrazinederivatives, cytoprotective agents, DNA topoisomerase inhibitors,biological response modifiers, retinoids, rexinoids, monoclonalantibodies, protein-tyrosine kinase inhibitors, porfimer sodium,mitotane (o, p′-ddd), and arsenic trioxide. Exemplary diagnostic agentsinclude in vivo diagnostic aids, in vivo diagnostic biologicals, andradiopaque agents.

Representative antibacterial substances are beta-lactam antibiotics,tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin,sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone,nalidixic acid, penicillin, tetracycline, oxytetracycline,chlorotetracycline, erythromycin, cephalosporins and analogs and theantimicrobial combination of fludalanine/pentizidone. Otherrepresentative antibacterial agents include of the poorly water-solublepyrridone-carboxylic acid type such as benofloxacin, nalidixic acid,enoxacin, ofloxacin, amifloxacin, flumequine, tosfloxacin, piromidicacid, pipemidic acid, miloxacin, oxolinic acid, cinoxacin, norfloxacin,ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin, danofloxacin,binfloxacin, sarafloxacin, ibafloxacin, difloxacin and salts thereof.

Representative antiparasitic compounds are ivermectin, bephenium,hydroxynaphthoate, praziquantel, nifurtimox, benznidasol, dichlorophenand dapsone. Representative anti-malarial compounds are4-aminoquinolines, 8-aminoquinolines and pyrimethamine.

Representative antiviral compounds are protease inhibitors,neuramidinase inhibitors, commercially available compounds, acyclovirand interferon.

Representative anti-inflammatory drugs include specific or selectiveCOX-2 receptor inhibitors, rofecoxib, celecoxib, etodolac, flurbiprofen,ibuprofen, ketoprofen, ketorolac, nabumetone, piroxicam, suprofen,tolmetin, zileuton, steroids, cyclooxygenase inhibitors, cortisone,hydrocortisone, betamethasone, dexamethasone, fluocortolone,prednisolone, phenylbutazone, triamcinolone, sulindac, indomethacin,salicylamide, naproxen, colchicine, fenoprofen, diclofenac, indoprofen,dexamethasone, allopurinol, oxyphenbutazone, probenecid and sodiumsalicylamide.

Representative analgesic drugs are diflunisal, aspirin, ibuprofen,profen-type compounds, morphine, codeine, levorphanol, hydromorphone,oxymorphone, oxycodone, hydrocodone, naloxene, levallorphan, etorphine,fentanyl, bremazocine, meperidine, nalorphine, tramadol, andacetaminophen.

Representative antihistamines and decongestants are acrivastine,astemizole, norastemizol, brompheniramine, cetirizine, clemastine,diphenhydramine, ebastine, famotidine, fexofenadine, meclizine,nizatidine, perilamine, promethazine, ranitidine, terfenadine,chlorpheniramine, cimetidine, tetrahydrozoline, tripolidine, loratadine,desloratadine, antazoline, and pseudoephedrine.

Representative antiasthma drugs are theophylline, ephedrine,beclomethasone dipropionate and epinephrine.

Representative anticoagulants are heparin, bishydroxycoumarin, andwarfarin.

Representative psychic energizers are isocoboxazid, nialamide,phenelzine, imipramine, tranycypromine, and parglyene.

Representative anticonvulsants are clonazepam, phenobarbital,mephobarbital, primidone, enitabas, diphenylhydantion, ethltion,pheneturide, ethosuximide, diazepam, phenyloin carbamazepine,lamotrigine, lorazepam, levetiracetam, oxcarbazepine, topiramate,valproic acid, chlorazepate, gabapentin, felbamate, tiagabine andzonisamide.

Representative antidepressants are amitriptyline, chlordiazepoxideperphenazine, protriptyline, imipramine, doxepin, venlafaxine,o-desmethyl venlafaxine, citalopram, escitalopram, bupropion,clomipramine, desipramine, nefazodone, fluoxetine, fluvoxamine,maprotiline, mirtazapine, nortriptyline, paroxetine, phenelzine,tranylcypromine, sertraline, trazodone, trimipramine, and amoxapine.

Representative antidiabetics are sulphonylureas, such as tolbutamide,chlorpropamide, tolazamide, acetohexamide, glibenclamide, gliclazide,1-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide, glyburide,gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide,glymidine, glypinamide, phenbutamide, and tolcyclamide;thiazolidinediones (glitazones), such as rosiglitazone, pioglitazone,and troglitazone; biguanidines, such as metformin; and otherantidiabetic agents, such as nateglinide, repaglinide, insulin,somatostatin and its analogs, chlorpropamide, isophane insulin,protamine zinc insulin suspension, globin zinc insulin, and extendedinsulin zinc suspension.

Representative antineoplastics are chlorambucil, cyclophosphamide,triethylenemelamine, thiotepa, hexamethyl-melamine, busulfan,carmustine, lomustine, dacarbazine, arabinoside cytosine,mercaptopurine, azathiprine, vincristine, vinblastine, taxol, etoposide,actinomycin D, daunorubicin, doxorubicin, bleomycin, mitomycin;cisplatin; hydroxyurea, procarbazine, aminoglutethimide, tamoxifen,adriamycin, fluorouracil, methotrexate, mechlorethamine, uracil mustard,5-fluorouracil, 6-6-thioguanine and procarbazine asparaginase.

Representative steroidal drugs are prednisone, prednisolone, cortisone,cortisol and triamcinolone; androgenic steroids such as methyltesterone,testosterone, and fluoxmesterone; estrogenic steroids such as17β-estradiol, α-estradiol, estriol, α-estradiol 3 benzoate, and17-ethynylestradiol-3-methyl ether; progestational steriods such asprogesterone, 19-nor-pregn-4-ene-3,20-dione,17-hydroxy-19-nor-17-α-pregn-5(10)-ene-20-yn-3-one,17α-ethynyl-17-hydroxy-5(10)-estren-3-one, and 9β,10α-pregna-4,6-diene-3,20-dione.

Representative estrogen antagonist-agonist drugs are clomiphene citrateand raloxifene HCl.

Representative antipsychotics are prochlorperazine, lithium carbonate,lithium citrate, thioridazine, molindone, fluphenazine, trifluoperazine,perphenazine, amitriptyline, trifluopromazine, chlorpromazine,clozapine, haloperidol, loxapine, mesoridazine, olanzapine, quetiapine,ziprasidone, risperidone, pimozide, mesoridazine besylate,chlorprothixene, and thiothixene.

Representative hypnotics and sedatives are pentobarbital sodium,phenobarbital, secobarbital, thiopental, heterocyclic hypnotics,dioxopiperidines, imidazopyridines, such as zolpidem tartrate,glutarimides, diethylisovaleramide, α-bromoisovaleryl urea, urethanes,disulfanes.

Representative antihypertensives are nifedipine, verapamil, diltiazem,felodipine, amlodipine, isradipine, nicardipine, nisoldipine,nimodipine, bepridil, enalapril, captopril, lisinopril, benazepril,enalaprilat, espirapril, fosinopril, moexipril, quinapril, ramipril,perindopril, trandolapril, furosemide, bumetanide, ethacrynic acid,torsemide, muzolimide, azosemide, piretanide, tripamide,hydrochlorothiazide, chlorthalidone, indapamide, metozalone,cyclopenthiazide, xipamide, mefruside, dorzolamide, acetazolamide,methazolamide, ethoxzolamide, cyclothiazide, clopamide,dichlorphenamide, hydroflumethiazide, trichlormethiazide, polythiazide,benzothiazide, spironolactone, methyldopa, hydralazine, clonidine,chlorothiazide, deserpidine, timolol, propranolol, metoprolol, pindolol,acebutolol, prazosin hydrochloride, methyl dopa(L-β-3,4-dihydroxyphenylalanine), pivaloyloxyethyl ester of α-methyldopahydrochloride dihydrate, candesartan cilexetil, eprosartan mesylate,losartan potassium, olmersartan medoxomil, telmisartan, valsartan, andreserpine.

Representative anti-incontinence agents include oxybutynin.

Representative tranquilizers are chloropromazine, promazine,fluphenazine, reserpine, deserpidine, meprobamate, and benezodiazepines(anxyiolitic, sedatives, and hypnotics) such as alprazolam,chlordiazepoxide, diazepam, lorazepam, oxazepam, temazepam, andtriazolam.

Representative anti-spasmodics and muscle contractants are atropine,scopolamine, methscopolamine, oxyphenonium, papaverine, andprostaglandins such as PGE₁ PGE₂ PGF_(1α), PGF_(2α), and PGA.

Representative local anesthetics are benzocaine, procaine, lidocaine,maepaine, piperocaine, tetracaine and dibucaine.

Representative muscle relaxants are alcuronium, alosetron,aminophylline, baclofen, carisoprodol, chlorphenesin, chlorphenesincarbamate, chlorzoxazone, chlormezanone, dantrolene, decamethonium,dyphylline, eperisione, ethaverine, gallamine triethiodide,hexafluorenium, metaxalone, metocurine iodide, orphenadrine,pancuronium, papaverine, pipecuronium, theophylline, tizanidine,tolperisone, tubocurarine, vecuronium, idrocilamide, ligustilide,cnidilide, senkyunolide, succinylcholine-chloride, danbrolene,cyclobenzaprine, methocarbamol, diazepam, mephenesin, methocarbomal,trihexylphenidyl, pridinol (pridinolum), and biperiden.

Representative anti-Parkinson agents are carbidopa, levodopa,ropinirole, pergolide mesylate, rasagiline, pramipexole, entacapone,benzacide, bromocriptine, selegiline, amantadine, trihexylphenidyl,biperiden, pridinol mesylate, and tolcapone.

Representative anti-Dementia and anti-Alzheimer disease agents arememantine, donepexil, galantamine, rivastigmine, and tacrineRepresentative sympathomimetic drugs are albuterol, epinephrine,amphetamine ephedrine and norepinephrine.

Representative cardiovascular drugs are procainamide, procainamidehydrochloride, amyl nitrite, nitroglycerin, dipyredamole, sodium nitrateand mannitol nitrate.

Representative diuretics are chlorothiazide, acetazolamide,methazolamide, triamterene, furosemide, indapamide, and flumethiazide.

Representative β-blockers are caravedilol, pindolol, propranolol,practolol, metoprolol, esmolol, oxprenolol, timolol, atenolol,alprenolol, and acebutolol.

Representative phosphodiesterase inhibitors are vardenafil HCl andsildenafil citrate.

Representative antilipemic agents are atorvastatin, cerivastatin,clofibrate, fluvastatin, gemfibrozil, lovastatin, mevinolinic acid,niacin, pravastatin, and simvastatin.

Representative antigout drugs are colchicine, allopurinol, probenecid,sulfinpyrazone, and benzbromadone.

Representative nutritional agents are ascorbic acid, niacin,nicotinamide, folic acid, choline biotin, panthothenic acid, and vitaminB₁₂, essential amino acids; essential fats.

Representative electrolytes are calcium gluconate, calcium lactate,potassium chloride, potassium sulfate, sodium chloride, potassiumfluoride, ferrous lactate, ferrous gluconate, ferrous sulfate, ferrousfumurate and sodium lactate.

Representative drugs that act on α-adrenergic receptors are clonidinehydrochloride, prazosin, tamsulosin, terazosin, and doxazosin.

Representative mild CNS stimulants are caffeine, modafinil, andmethylphenidate hydrochloride.

The formulation of the invention can also be used with unclassifiedtherapeutic agents such as clopidrogel, which is indicated for thereduction of atherosclerotic events (myocardial infarction, stroke, andvascular death) in patients with atherosclerosis documented by recentstroke, recent myocardial infarction, or established peripheral arterialdisease.

The active agents (drugs) listed herein should not be consideredexhaustive and is merely exemplary of the many embodiments consideredwithin the scope of the invention. Many other active agents can beadministered with the formulation of the present invention. Suitabledrugs are selected from the list of drugs included herein as well asfrom any other drugs accepted by the U.S.F.D.A. or other similarlyrecognized authority in Canada (Health Canada), Mexico (MexicoDepartment of Health), Europe (European Medicines Agency (EMEA)), SouthAmerica (in particular in Argentina (Administración Nacional deMedicamentos, Alimentos y Tecnología Médica (ANMAT) and Brazil(Ministério da Saúde)), Australia (Department of Health and Ageing),Africa (in particular in South Africa (Department of Health) and Zimbawe(Ministry of Health and Child Welfare),) or Asia (in particular Japan(Ministry of Health, Labour and Welfare), Taiwan (Executive YuansDepartment of Health), and China (Ministry of Health People's Republicof China)) as being suitable for administration to humans or animals.Preferred embodiments of the invention include those wherein the activesubstance is pharmacologically or biologically active or wherein theenvironment of use is the GI tract of a mammal.

The amount of therapeutic compound incorporated in each dosage form willbe at least one or more unit doses and can be selected according toknown principles of pharmacy. An effective amount of therapeuticcompound is specifically contemplated. By the term “effective amount”,it is understood that, with respect to, for example, pharmaceuticals, apharmaceutically effective amount is contemplated. A pharmaceuticallyeffective amount is the amount or quantity of a drug or pharmaceuticallyactive substance which is sufficient to elicit the required or desiredtherapeutic response, or in other words, the amount which is sufficientto elicit an appreciable biological response when administered to apatient. The appreciable biological response may occur as a result ofadministration of single or multiple unit doses of an active substance.A dosage form according to the invention that comprises two or moreactive agents can include subtherapeutic amounts of one or more of thoseactive agents such that an improved, additive or synergistic clinicalbenefit is provided by the dosage form. By “subtherapeutic amount” ismeant an amount less than that typically recognized as being therapeuticon its own in a subject to which the dosage form is administered.Therefore, a dosage form can comprise a subtherapeutic amount of a firstdrug and a therapeutic amount of a second drug. Alternatively, a dosageform can comprise a subtherapeutic amount of a first drug and asubtherapeutic amount of a second drug.

The term “unit dose” is used herein to mean a dosage form containing aquantity of the therapeutic compound, said quantity being such that oneor more predetermined units may be provided as a single therapeuticadministration.

The active agent can be present in any particle size suitable forhot-melt extrusion. Fine particle sizes and larger particle sizes can beused. It can be added as a liquid, solid, emulsion, or any othersuitable form.

There are several methods well known in the pharmaceutical literaturefor producing fine drug particles in the micro or nanometer size range.These methods can be divided into three primary categories: (1)mechanical micronization (2) solution based phase separation and (3)rapid freezing techniques. Drug particles made according to any of thesetechniques will be suitable for use in the present pharmaceuticalcomposition.

Such processes include mechanical milling by ball mill, jet mill, orother similar grinding process; solution based phase separationtechniques such as spray drying, emulsification/evaporation,emulsification/solvent extraction, complex coacervation, gas antisolventprecipitation (GAS), precipitation with a compressed antisolvent (PCA),aerosol solvent extraction system (ASES), evaporative precipitation intoaqueous solution (EPAS), supercritical antisolvent (SAS),solution-enhanced dispersion by supercritical fluids (SEDS), rapidexpansion from supercritical to aqueous solutions (RESAS), pressureinduced phase separation (PIPS); or freezing techniques such as sprayfreezing into liquid (SFL) and ultra rapid freezing (URF). Detaileddescriptions of these methods are included in references cited herein,the entire disclosures of which are hereby incorporated by reference.

Mechanical micronization is most commonly done by milling techniquesthat can produce particles in the range of 1 to 20 microns. The mostcommon processes utilized for this type of mechanical particle sizereduction are ball and jet milling.

There are many solution based phase separation processes documented inthe pharmaceutical literature for producing micro and nano-sized drugparticles. Some of the more commonly known processes are spray drying,emulsification/evaporation, emulsification/solvent extraction, andcomplex coacervation. Some of the lesser-known processes are, for thesake of brevity, listed below along with their respective illustratingreferences: a) gas antisolvent precipitation (GAS)— and WO9003782EP0437451 EP0437451 DK59091; b) precipitation with a compressedantisolvent (PCA)—and U.S. Pat. No. 5,874,029; c) aerosol solventextraction system (ASES)—; d) evaporative precipitation into aqueoussolution (EPAS)— US patent application 20040067251; e) supercriticalantisolvent (SAS)—; f) solution-enhanced dispersion by supercriticalfluids (SEDS)—; and g) rapid expansion from supercritical to aqueoussolutions (RESAS)—.

Freezing techniques for producing micro or nano-sized drug particles arelisted below along with their respective illustrating references: a)spray freezing into liquid (SFL)—WO02060411 USPTO App. # 2003054042 and2003024424; and b) ultra rapid freezing (URF).

Drug-containing particles may or may not undergo substantial aggregationor agglomeration during hot-melt extrusion and/or will be disaggregatedto essentially primary particles during hot-melt extrusion due to theintense mixing and agitation that occurs during the process. In somecases, the extrudate may need to be processed more than one time throughthe extruder in order to provide the desired degree of disaggregation.As used herein, the term “disaggregate”, as used in reference to thedrug-containing particles, means to reduce a loosely bound agglomerateto essentially its primary constituent particles. As used herein, theterm “to agglomerate” or “agglomeration”, as used in reference to thedrug-containing particles means individual particles form a largerparticle.

In view of the above description and the examples below, one of ordinaryskill in the art will be able to practice the invention as claimedwithout undue experimentation. The foregoing will be better understoodwith reference to the following examples that detail certain proceduresfor the preparation of formulations according to the present invention.All references made to these examples are for the purposes ofillustration. The following examples should not be consideredexhaustive, but merely illustrative of only a few of the manyembodiments contemplated by the present invention.

Example 1 Preparation of the Excipient Mixture

Method A. Wet Granulation with Water.

A bioadhesive alkaline thermoplastic polymer is wet granulated withwater, and an acidic component under high shear until the ingredientswere uniformly mixed. One or more other bioadhesive polymers areoptionally included in the granulation. One or more other thermoplasticpolymers are optionally included in the granulation. One or more otheralkaline polymers are optionally included in the granulation. One ormore antioxidants are included in the granulation. One or moreplasticizers are optionally included in the granulation. One or moreexcipients are optionally included in the granulation. Aftergranulations, the granulate is optionally dried.

Method B. Wet Granulation with Buffer.

The process of Method A is followed except that a buffer rather thanwater is used as the liquid medium used for granulation.

Method C. Wet Granulation with Aqueous Organic Solvent.

The process of Method A or Method B is followed except that a watermiscible organic solvent is included in the liquid medium used forgranulation. The liquid medium can comprise a major portion of water (orbuffer) or organic solvent. The liquid medium generally contains atleast 5% water (or buffer).

Method D. Wet Granulation with an Aqueous Mineral Acid Solution.

The process of Method A or Method B is followed except that an aqueoussolution containing mineral acid is used as the liquid granulationmedium.

Method E. Hydroalcoholic Wet Granulation with a Mineral Acid.

The process of Method A or Method B is followed except that a watermiscible organic solvent is included in the mineral acid liquid mediumfor granulation. The liquid medium can comprise a major portion ofwater, mineral acid or organic solvent. The liquid granulation mediumgenerally contains at least 5% water.

Method F. Wet Granulation with a Mineral Acid in the Presence of anAlkaline Labile Drug.

The process of Method A or Method B is followed except that a mineralacid is used as the liquid granulation medium and the acid labile drugis present during the granulation step.

Method G. Hydroalcoholic Wet Granulation with a Mineral Acid in thePresence of an Alkaline Labile Drug

The process of Method A or Method B is followed except that a watermiscible organic solvent is included in the mineral acid liquid mediumfor granulation and the acid labile drug is present during thegranulation step. The liquid medium can comprise a major portion ofwater, mineral acid or organic solvent. The liquid granulation mediumgenerally contains at least 5% water.

Method H. Dry Granulation

A bioadhesive alkaline thermoplastic polymer and an acidic component aredry granulated under high shear until the ingredients were uniformlymixed. One or more other bioadhesive polymers are optionally included inthe granulation. One or more other thermoplastic polymers are optionallyincluded in the granulation. One or more other alkaline polymers areoptionally included in the granulation. One or more antioxidants areincluded in the granulation. One or more plasticizers are optionallyincluded in the granulation. One or more excipients are optionallyincluded in the granulation.

Example 2

The following process was used to prepare a hot-melt extrudedcomposition according to the invention. The following ingredients in theamounts indicated were used in preparing hot-melt extruded control andsample compositions containing testosterone (Ts) as the active agent.

Method A.

An excipient mixture prepared according to Example 1 is mixed with analkaline labile drug and blended under high shear to form a uniformblend. The blend is hot-melt extruded using an extruder equipped with afilm (sheet) die.

Method B.

Method A is followed with the following exceptions. A RandcastleTaskmaster hot-melt extruder equipped with a 6-inch flat die wasoperated at 60-90 RPM, 6-9 Drive Amps with an Extrusion Temperature fromabout 65-135° C. to prepare the composition. All powders were blended ina v-shell blender prior to extrusion. Temperature zones were set asfollows: zone 1: 65° C., zone 2: 120° C., zone 3: 125° C., zone 4: 135°C., die temperature 135° C. The powder blend was placed in a feed hopperthat is located at the head of a horizontal screw such that the materialis starve fed by a mass flow controller operated at 1.5 kg/hr. Theresidence time of the material in the extruder was approximately threeto five minutes. The extrudate was cut into approximately one-footsections after exiting the die and placed on an aluminum sheets andallowed to cool at ambient conditions. In one embodiment, the granulatedwet mass was placed in the feed hopper.

Example 3 Method A

The combined processes of Examples 1 and 2 are used to prepare ahot-melt extruded composition according to the invention. The followingingredients in the amounts indicated were used in preparing hot-meltextruded control and sample compositions containing testosterone (Ts) asthe active agent.

Raw Material % w/w Testosterone, USP 15.00 Polyethylene Oxide 64.00(PolyOx WSR N80, WSR N12K, WSR 301) Carbopol 974P 10.00 Vitamin ESuccinate 5.00 Titanium Dioxide 1.00 Poloxamer 407 5.00

Testosterone and any other ingredients were added to the wet granulatedexcipient mixture prepared according to Example 1. The blend wasextruded as a monolayer film using a having a barrel temperature of 135°C. The moisture content of the blend prior to extrusion was 3.1%. TheHME composition is then analyzed by HPLC according to Example 4 todetermine the amount of degradants present.

The PEO can be a single grade of PEO or it can comprise two, three ormore different grades of PEO, e.g. PEO Grade 1, PEO Grade 2, PEO Grade3. The amount of each individual grade can be selected from thoseamounts disclosed herein.

Method B. Use of Two Acidic Components (Acidic Organic Acid, AcidicPolymer) and an Antioxidant

Raw Material % w/w Testosterone, USP 15.00 Polyethylene Oxide 64.00(PolyOx WSR N80, WSR N12K, WSR 301) Carbopol 974P 10.00 Citric AcidMonohydrate 1.00 Butylated Hydroxytoluene 4.00 Titanium Dioxide 1.00Poloxamer 407 5.00

The procedure of Example 1 was followed except that citric acid wasadded as a secondary acidifier and butylated hydroxytoluene was added asan antioxidant in place of Vitamin E succinate. As above, the excipientmixture was prepared by wet granulating the PolyOx and Poloxamer with 5%water under high shear. Carbopol was added and blended until uniform.

The amount of each individual grade of PEO can be selected from thoseamounts disclosed herein.

Method C. Use of Two Acidic Components (Non-Polymeric Organic Acid,Acidic Polymer) without an Antioxidant

The procedure of Example 1 was followed except that citric acid wasadded as a secondary acidifier. As above, the lot was prepared by wetgranulating the PolyOx and Poloxamer with 5% water under high shear.Carbopol was added and blended until uniform. The total amount of PEOpresent in the reservoir layer is 64% wt. of the layer.

Raw Material % w/w Testosterone, USP 15.00 PEO (PolyOx WSR N80) 26.85PEO (PolyOx WSR 301) 16.79 Carbopol 974P 10.00 Citric Acid Monohydrate5.00 Titanium Dioxide 1.00 Poloxamer 407 5.00

Method D

This method is similar to that of Examples 1 and 2 and Method C of thisexample, with the following exceptions.

Raw Material % w/w Testosterone, USP 15.00 Polyethylene Oxide (PolyOxWSR) 64.00 Carbopol 974P 10.00 Butylated Hydroxytoluene 4.00 TitaniumDioxide 1.00 Poloxamer 407 6.00

Method E

This method is similar to that of Examples 1 and 2, with the followingexceptions.

Raw Material % w/w Testosterone, USP 15.00 PEO (PolyOx WSR N80) 26.85PEO (PolyOx WSR N12K) 18.86 PEO (PolyOx WSR 301) 16.79 Carbopol 974P10.00 Butylated Hydroxytoluene 4.00 Titanium Dioxide 1.00 Poloxamer 4077.50

The total amount of PEO present in the reservoir layer is 62.5% wt. ofthe layer.

Method F.

This method is similar to that of Examples 1 and 2, with the followingexceptions.

Raw Material % w/w Testosterone, USP 15.00 PolyOx WSR N80 26.85 PolyOxWSR N12K 19.36 PolyOx WSR 301 16.79 Carbopol 974P 10.00 ButylatedHydroxytoluene 2.00 Titanium Dioxide 1.00 Poloxamer 407 9.00

The total amount of PEO present in the reservoir layer is 63% wt. of thelayer.

Method G

This method is similar to that of Examples 1 and 2 and Method F of thisexample, with the following exceptions. In this example, the liquidmedium was added as a bolus or in sequential portions to the granulationingredients.

Raw Material % w/w Testosterone, USP 15.00 Polyethylene Oxide (PolyOxWSR) 63.00 Carbopol 974P 10.00 Vitamin E 2.00 Titanium Dioxide 1.00Poloxamer 407 9.00

Method H

The same procedure or Method G was followed except that water andalcohol (ethanol) (50:50) was used as the liquid medium for granulation.

Example 4 Determination of Drug Stability

Twenty doses were sampled from a HME composition at the beginning,middle and end of the extrusion run a formulation. Composites of 10doses were analyzed in duplicate for impurities by HPLC at each timepoint. The weight percent for each degradant was determined. Specificdegradants analyzed include: 6B-Hydroxy-testosterone,4-Androsten-16-alpha-ol-3,17-dione, Epi-Testosterone and unidentifieddegradants. The HPLC method employed will vary according to the drugincluded in the HME composition. Such methods are found in HPLC in thePharmaceutical Industry (edited by Godwin W. Fong, Stanley K. Lam, NewYork: M. Dekker, 1991) or HPLC Methods for Pharmaceutical Analysis (byGeorge Lunn and Norman R. Schmuff. New York: John Wiley & Sons, 1997),the disclosures of which are hereby incorporated by reference.

Determination of Drug Release

Samples from the beginning, middle and end of a lot of extruded laminate(reservoir layer containing testosterone and backing layer excludingdrug) were sampled and dissolution studies were conducted in 1,000 mL ofSimulated Saliva Fluid (0.1% sodium lauryl sulfate at pH 6.75) at 100rpm using the paddles. Samples were withdrawal at 1, 2, 4, 6, 8, 12 and24 hours and assayed for testosterone content by HPLC.

Example 5 Preparation of a Backing Film Method A.

An exemplary backing film was prepared by hot-melt extrusion of ahydrophobic composition containing the following ingredients in thespecified amounts.

Raw Material % w/w PolyOx WSR N80 10.00 PolyOx WSR 205 7.50 PolyOx WSR301 36.50 Eudragit RS PO 35.00 Ethyl Cellulose Std 100 6.25 FD&C Red 40Lake 0.15 Titanium Dioxide 0.60 Citric Acid, monohydrate 1.00 DibutylSebacate 3.00

The total amount of PEO present in the backing layer is 62.5% wt. of thelayer.

The backing layer formulation was modified to minimize degradation ofalkaline labile drug, e.g. testosterone, at the interface between thebacking layer and the reservoir layer. The backing layer formulationincluded citric acid and the blend was wet granulated with water toacidify the polymers. These blends were extruded as a bilayer film at a3:1 drug layer to backing layer ratio and overall target thickness of1.20 mm using the Randcastle coextrusion line at 135° C. maximumprocessing temperature. The extruder was equipped with a dual manifoldflat (sheet-type) extrusion die. The moisture content of the blend priorto extrusion was 2.4%.

Example 6 Preparation of a Bi-Layered Laminate

An exemplary bi-layered laminate comprising a backing layer and areservoir layer was prepared by hot-melt coextrusion of a hydrophobiccomposition (as described in Example 5) and a hydrophilic composition,respectively, containing the following ingredients in the specifiedamounts.

Reservoir Layer (Hydrophilic Composition)

% w/w Compound Lot 1 Lot 2 Testosterone, USP 15.00 15.00 PolyOx WSR N8026.85 26.85 PolyOx WSR N12K 18.36 18.36 PolyOx WSR 301 16.29 13.79Carbopol 974P 12.50 15.00 Vitamin E Succinate 3.00 3.00 Vitamin E 2.002.00 Titanium Dioxide 1.00 1.00 Poloxamer F127 5.00 5.00 Total 100.00100.00

The films were extruded with the acidified backing film formulation asdescribed above. The drug layer thickness was 1.10 mm and the backingfilm thickness was 0.40 mm. Doses were cut to provide 5.0, 7.5, 10.0,12.5 and 15 mg Testosterone doses. The total amount of PEO present inthe reservoir layer of Lot 1 is 61.5% wt. of the layer, and the totalamount of PEO present in the reservoir layer Lot 2 is 59% wt. of thelayer.

Example 7 Preparation of a Bi-Layered Laminate

A clinical formulation was modified to achieve a slower dissolutionprofile. The testosterone concentration was lowered from 15% to 8.18%and the Carbopol concentration was increased from 10% to 15%. The batchwas prepared using Diosynth sourced testosterone by wet granulationacidification with 5%, 50 mM hydrochloric acid and 5% ethanol. Thegranulation was coextruded with the acidified backing film. These blendswere coextruded as a bi-layered laminate at a 2.75:1 drug layer tobacking layer ratio and overall target thickness of 1.50 mm using theRandcastle coextrusion line at 135° C. maximum processing temperature.The moisture content of the blend prior to extrusion was 2.0%.

Example 8 Preparation of a Bi-Layered Laminate

The methods of Examples 5 and 6 followed to prepare a bi-layeredlaminate comprising the following ingredients in the specified amounts.The total amount of PEO present in the reservoir layer is 65.82% wt. ofthe layer, and the total amount of PEO present in the backing layer is54% wt. of the layer.

Reservoir Layer

Raw Material % w/w Testosterone, USP 8.18 Polyethylene Oxide (PolyOxWSR) 65.82 Carbopol 974P 15.00 Vitamin E Succinate 5.00 Titanium Dioxide1.00 Poloxamer 407 5.00

Backing Layer

Raw Material % w/w PolyOx WSR N80 10.00 PolyOx WSR 205 7.50 PolyOx WSR301 36.50 Eudragit RS PO 35.00 Ethyl Cellulose Std 100 6.25 FD&C Red 40Lake 0.15 Titanium Dioxide 0.60 Citric Acid, monohydrate 1.00 DibutylSebacate 3.00

Example 9 Preparation of a Bi-Layered Laminate

The methods of Examples 5 and 6 followed to prepare a bi-layeredlaminate comprising the following ingredients in the specified amounts.

Reservoir Layer

Raw Material % w/w Testosterone, USP 8.18 PolyOx WSR N80 23.67 PolyOxWSR N12K 20.36 PolyOx WSR 301 16.79 Carbopol 974P 15.00 GlycerylMonooleate 5.00 Vitamin E Succinate 5.00 Titanium Dioxide 1.00 Poloxamer407 5.00

The melt viscosity of the formulation was significantly increased ascompared to another formulation containing less Carbopol. Processingconditions were modified to avoid over pressurizing the extruder. Thescrew speed was increased by 22% and the feed rate was decreased by 46%to achieve acceptable pressure at the adapter. The total amount of PEOpresent in the reservoir layer is 60.82% wt. of the layer.

Example 10 Exemplary Method for Hot-Melt Extrusion of a Reservoir Layer

A Randcastle Taskmaster hot-melt extruder equipped with a 6 inch flatdie was operated at 60-90 RPM, 6-9 Drive Amps with an ExtrusionTemperatures from 65-135° C. to prepare the composition. All powderswere blended in a v-shell blender prior to extrusion. Temperature zoneswere set as follows: zone 1: 65° C., zone 2: 120° C., zone 3: 125° C.,zone 4: 135° C. die temperature 135° C. The powder blend was placed in ahopper that is located at the head of a horizontal screw such that thematerial is starve fed by a mass flow controller operated at 1.5 kg/hr.The residence time of the material in the extruder was approximatelythree to five minutes. The extrudate was cut into approximately one footsections after exiting the die and placed on an aluminum sheets andallowed to cool at ambient conditions.

Example 11 Exemplary Method for Hot-Melt Extrusion of a Backing Layer

A Randcastle Taskmaster hot-melt extruder equipped with a 6 inch flatdie was operated at 60-90 RPM, 6-9 Drive Amps with an ExtrusionTemperatures from 65-135° C. to prepare the composition. All powderswere blended in a v-shell blender prior to extrusion. Temperature zoneswere set as follows: zone 1: 65° C., zone 2: 120° C., zone 3: 130° C.,zone 4: 130° C., adapter: 135° C., transfer tube: 135° C., dietemperature 140° C. The powder blend was placed in a hopper that islocated at the head of a horizontal screw such that the material isstarve fed by a mass flow controller operated at 0.5 kg/hr. Theresidence time of the material in the extruder was approximately fiveminutes. The extrudate was cut into approximately one-foot sectionsafter exiting the die and placed on an aluminum sheets and allowed tocool at ambient conditions.

Example 12 Exemplary Formulations for a Stabilized Composition of theInvention

Method A.

Raw Material % w/w Alkaline labile drug 0.001-50    AlkalineThermoplastic Bioadhesive Polymer   10-99.9 Acidic Component 0.001-10   Optional Hydrophilic polymer 0-75 Optional Hydrophobic polymer 0-75Optional bioadhesive polymer 0-50 Optional Thermoplastic Polymer (or0-60 matrix-forming material) Optional Plasticizer 0-25 OptionalAntioxidant 0-10 Optional thermal lubricant 0-20 Optional Opaquant 0-5 

Method B.

Raw Material % w/w Alkaline labile drug 0.001-50    PEO 10-99  OptionalHydrophilic polymer 0-75 Optional Hydrophobic polymer 0-75 Optionalbioadhesive polymer 0-50 Optional Thermoplastic Polymer (or 0-60matrix-forming material) Acidic Component 0.001-10    OptionalPlasticizer 0-25 Optional Antioxidant 0-10 Optional thermal lubricant0-20 Optional Opaquant 0-5 

Method C.

Raw Material % w/w Alkaline labile drug 0.001-50    PEO   10-99.9Optional Hydrophilic polymer 0-75 Optional Hydrophobic polymer 0-75Polymeric Acidic Component 0.25-35   Non-polymeric acidic component0.001-10    Optional bioadhesive polymer 0-50 Optional ThermoplasticPolymer (or 0-60 matrix-forming material) Optional thermal lubricant0-20 Optional Antioxidant 0-10 Optional Plasticizer 0-20 OptionalOpaquant 0-5 

One or both acidic components are present in the above formulation.

Method D.

Raw Material % w/w Alkaline labile drug 0.001-50    PEO Grade 1 5-50 PEOGrade 2 5-50 PEO Grade 3 5-50 Polymeric Acidic Component 0.25-35  Non-polymeric Acidic Component 0.001-10    Optional Hydrophilic polymer0-75 Optional Hydrophobic polymer 0-75 Optional bioadhesive polymer 0-50Optional Thermoplastic Polymer (or 0-60 matrix-forming material)Optional Thermal Lubricant 0-20 Optional Plasticizer 0-20 OptionalAntioxidant 0-10 Optional Opaquant 0-5 

Three different grades of PEO are present in the above formulation. Oneor both acidic components are present in the above formulation.

Method E.

Raw Material % w/w Alkaline labile drug 0.001-50    PEO Grade 1 5-50 PEOGrade 2 5-50 PEO Grade 3 5-50 CARBOPOL 0.25-35   Non-polymeric AcidicComponent 0.001-10    POLOXAMER 0.25-20   Optional Hydrophobic polymer0-75 Optional Bioadhesive Polymer 0-50 Optional Thermoplastic Matrix-0-60 Forming Material Optional Thermal Lubricant 0-20 OptionalPlasticizer 0-20 Optional Antioxidant 0-10 Optional Opaquant 0-5 

The formulation comprises three different grades of PEO, a polymericacidic component, a non-polymeric organic acid, a hydrophilic polymer,an alkaline labile drug, and optionally one or more the other componentslisted in the above table.

Example 13 Exemplary Formulations for a Backing Layer of the Invention

Method A.

Raw Material % w/w Thermoplastic Polymer  10-99.9 Hydrophobic polymer0.1-99.9 Optional Hydrophilic polymer 0-50 Optional ThermoplasticPolymer 0-75 Optional Acidic Component 0-10 Optional Plasticizer 0-20Optional Antioxidant 0-10 Optional thermal lubricant 0-20 OptionalOpaquant 0-5 

Method B.

Raw Material % w/w Polyethylene Oxide   5-99.9 Hydrophobic polymer0.1-99.9 Optional Hydrophilic polymer 0-50 Optional ThermoplasticPolymer 0-75 Optional Acidic Component 0-10 Optional Plasticizer 0-20Optional Antioxidant 0-10 Optional thermal lubricant 0-20 OptionalOpaquant 0-5 

Method C.

Raw Material % w/w PEO Grade 1 5-50 PEO Grade 2 5-50 PEO Grade 3 5-50Hydrophobic polymer 0.1-99.9 Optional Hydrophilic polymer 0-50 OptionalThermoplastic Polymer 0-75 Optional Acidic Component 0-10 OptionalPlasticizer 0-20 Optional Antioxidant 0-10 Optional thermal lubricant0-20 Optional Opaquant 0-5 

Three different grades of PEO are present and the hydrophobic polymer isalso present.

Method D.

Raw Material % w/w PEO Grade 1 5-50 PEO Grade 2 5-50 PEO Grade 3 5-50Polyacrylate polymer 10-85  Ethyl Cellulose 1-85 Optional ThermoplasticPolymer 0-75 Optional Acidic Component 0-10 Optional Plasticizer 0-20Optional Antioxidant 0-10 Optional thermal lubricant 0-20 OptionalOpaquant 0-5 

Three different grades of PEO are present.

The above is a detailed description of particular embodiments of theinvention. It will be appreciated that, although specific embodiments ofthe invention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims. All of the embodiments disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure.

1-61. (canceled) 62) A stabilized hot-melt extruded pharmaceutical composition comprising: a hot-melt extrusion of (i) a non-alkaline theroplastic bioadhesive matrix comprising a preformed excipient mixture comprising an alkaline thermoplastic bioadhesive polymer and an acidic component; mixed with (ii) an alkaline labile drug and optionally one or more other components; wherein the pharmaceutical composition comprises the matrix in an amount from 50-99.999 wt % and the drug in an amount from 0.001-50 wt. %. 63) The composition of claim 62, wherein the excipient mixture further comprises a hydrophilic polymer. 64) The composition of claim 62, wherein the composition comprises two or more thermoplastic and water swellable, water soluble, or water erodible polymers. 65) The composition of claim 62, wherein the alkaline thermoplastic bioadhesive polymer is PEO. 66) The composition of claim 65, wherein the PEO is selected from the group consisting of PEO grade 1, PEO grade 2 and PEO grade 3, wherein PEO Grade 1 is polyethylene oxide with a solution viscosity in the range of 12-8800 mPa·s at 25 [deg.]C in a 5% solution or approximate molecular weight range from 100,000-600,000; PEO Grade 2 is polyethylene oxide with a solution viscosity in the range of 8800 mPa'S at 25 [deg.]C in a 5% solution to 4000 mpa-s at 25 [deg.]C in a 2% solution or approximate molecular weight range from 900,000-2,000,000; and PEO Grade 3 is polyethylene oxide with a solution viscosity in the range of 1650-15,000 mpa-s at 25 [deg.]C in a 1% solution or approximate molecular weight range from 4,000,000-8,000,000. 67) The composition of claim 62, wherein the acidic component is selected from the group consisting of a polymeric organic acid, a non-polymeric organic acid, an inorganic acid, an acidic polymer, and a combination thereof. 68) The composition of claim 62 further comprising an opaquant. 69) The composition of claim 62, wherein the alkaline labile drug is selected from the group consisting of testosterone, oxybutynin, morphine, fentanyl, aspirin, lansoprazole, omeprazole, pantoprazole, rabeprazole and naltrexone. 70) A hot-melt extruded composition comprising the composition of claim 62 and a second composition, wherein the second composition comprises at least one hydrophobic polymer. 71) The hot-melt extruded composition of claim 70, wherein the hot-melt extruded composition is an immediate release, rapid release, or delayed release therapeutic composition. 72) The hot-melt extruded composition of claim 70, wherein the hot-melt extruded composition is a controlled, sustained, slow, extended, or targeted release therapeutic composition. 73) The hot-melt extruded composition of claim 70, wherein the hot-melt extruded composition is a dosage form adapted for transdermal, transmucosal, rectal, pulmonary, nasal, vaginal, ocular, or optic drug delivery, or as an implantable drug delivery device. 74) A process for preparing a stabilized bioadhesive hot-melt extruded composition comprising the steps of: a) wet or dry granulating at least one water swellable or water soluble alkaline matrix-forming material; at least one acidic component; and optionally one or more antioxidants, one or more hydrophobic polymers, one or more hydrophilic polymers, one or more other excipients, or a combination thereof to form an excipient mixture having a solution pH of 7 or less; b) mixing the excipient mixture with an alkaline labile drug to form a bioadhesive thermoplastic hydrophilic composition; and c) hot-melt extruding the hydrophilic composition to form the bioadhesive hot-melt extruded composition, wherein the matrix-forming material is thermoplastic, bioadhesive, or both. 75) The process according to claim 74, wherein the hot-melt extruding step comprises coextruding the bioadhesive hot-melt extruded composition and a thermoplastic hydrophobic second composition to form a bioadhesive bi-layered hot-melt coextruded laminate comprising a bioadhesive hydrophilic reservoir layer and a hydrophobic low permeability backing layer, respectively, wherein the thermoplastic hydrophobic second composition comprises at least one hydrophobic polymer, optionally a plasticizer, optionally one or more hydrophilic polymers, and optionally at least one acidic component, wherein the second composition excludes a drug. 76) The process of claim 75, wherein the granulation step is wet granulation and the wet granulation is conducted with water, buffer, an aqueous organic solvent, or a combination thereof. 77) The process of claim 75 further comprising the step of dividing the laminate into unit doses. 78) The process according to claim 74, further comprising the steps of: hot-melt extruding a second composition; and laminating the bioadhesive hot-melt extruded composition and second composition together to form a bioadhesive bi-layered hot-melt laminate comprising a bioadhesive hydrophilic reservoir layer and a hydrophobic low permeability backing layer, respectively, wherein the thermoplastic second composition comprises at least one hydrophobic polymer, optionally a plasticizer, optionally one or more hydrophilic polymers, and optionally at least one acidic component, wherein the second composition excludes a drug. 79) The process of claim 78, wherein the granulation step is wet granulation and the wet granulation is conducted with water, buffer, an aqueous organic solvent, or a combination thereof. 80) The process of claim 78 further comprising the step of dividing the laminate into unit doses. 81) A unit dose comprising a composition according to claim
 62. 